JP2010527928A - Novel combinations comprising phosphodiesterase-5 inhibitors and their use - Google Patents

Abstract

The present invention relates to novel pharmaceutical methods for the treatment of various conditions. At least one phosphodiesterase-5-inhibitor in the following agents: selective serotonin reuptake inhibitors; serotonin-noradrenaline reuptake inhibitors; cholinesterase inhibitors; dopamine agonists; or amino acids, monoamines, neuropeptides and synaptic clefts A composition comprising in combination with one or more of a drug suitable for increasing the chemical concentration of a neurotransmitter selected from other drugs capable of primary neurotransmission, and for the treatment of a neurodegenerative disease in a subject Their use for. The invention also includes a composition comprising at least one phosphodiesterase-5 inhibitor in combination with one or more of the following agents: a selective serotonin reuptake inhibitor; or a cholinesterase inhibitor, and damaged skin in a subject It also relates to their use for treating.

Description

(Cross-reference to related applications)
This application claims the benefit of US Patent Application No. 60 / 916,883, filed May 9, 2007, the entire contents of which are hereby incorporated by reference.

(Technical field)
The present invention relates generally to novel pharmaceutical compositions and methods for the treatment of various symptoms, disorders, and diseases, and more specifically one phosphodiesterase-5 inhibitor (PI-5). It relates to the treatment of such symptoms, disorders and diseases using therapeutic agents contained in combination with the above agents. In certain embodiments, PI-5 is at least one or more selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), cholinesterase inhibitors (CI), dopamine agonists (DI) or It is administered in combination with any suitable agent (OI) that increases the chemical concentration of other neurotransmitters, such as amino acids, monoamines, neuropeptides and other agents capable of primary neurotransmission in the synaptic cleft.

(Background of the Invention)
The nervous system consists of the central nervous system (CNS), which consists of the brain and spinal cord and serves as a collection point for nerve impulses, and the peripheral nervous system that includes all nerves except the brain or spinal cord and connects all parts of the body to the central nervous system (PNS). The peripheral (sensory) nervous system receives the stimuli first, then the central nervous system interprets those stimuli and the peripheral (motor) nervous system initiates a response.

  A neurotransmitter is a chemical that allows the transfer of information from one neuron across a gap between it and an adjacent neuron. Release of neurotransmitters from one area of a neuron and recognition of chemicals by receptor sites on adjacent neurons causes an electrical response that promotes neurotransmitter release and neurotransmitter movement across the gap cause. Thus, neurotransmitters are essential for signal transduction between neurons, and the specification of appropriate transmitters in distinguishing neurons has been associated with endogenous neuronal identity and exogenous signaling proteins. Thus, many diseases and disorders result from or are associated with neurotransmitter overproduction or underproduction.

  Acetylcholine is one example of a neurotransmitter that is particularly important in the stimulation of muscle tissue. After stimulation, acetylcholine breaks down into acetate and choline, which are absorbed into the first neuron to form another acetylcholine molecule. The poison curare interferes with the transmission of acetylcholine. Some nerve agents inhibit the degradation of acetylcholine, causing continuous stimulation of receptor cells and convulsions of the heart-like muscles. Epinephrine (adrenaline) and norepinephrine are neurotransmitters secreted mainly from the adrenal glands. Secretion causes an increase in heart rate and increased production of glucose as a rapid energy source (a “fight or escape” response). In addition, when another neurotransmitter, dopamine, promotes critical brain function and abnormal amounts are present, abnormal dopamine neurotransmission is present in Parkinson's disease, certain addictions, and schizophrenia May play a role. Serotonin is another representative neurotransmitter synthesized from the amino acid tryptophan and thought to play a biochemical role in mood and mood disorders, including anxiety, depression, and bipolar disorder.

  Neurodegenerative diseases are chronic degenerative diseases of the central nervous system that often lead to dementia. The causes and mechanisms of this brain disease population are not well understood, but they are increasing in the developed and underdeveloped world and are common in the aging population. These diseases are characterized by neuronal degeneration and molecular changes in neurons that ultimately result in neuronal dysfunction and cell death. Examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia with Parkinsonian features, progressive supranuclear palsy, essential dyskinesia, And dementia, but these are only examples, and there are a wide variety of less common but related symptoms.

  In recent years, there has been a lot of progress towards understanding neurodegenerative diseases, but there are few effective treatments currently available and there are no cures.

  In addition, the neuroimmune skin system (NS) is composed of the nervous system, the endocrine system, and the immune system, with each component functioning together as a single integrated unit rather than separate. Normal human skin expresses various neuropeptides, including neuromediators and neurohormones, which are derived directly from sensory neurons or from skin cells such as keratinocytes. Neuropeptides can be released retrogradely from peripheral nerves into the skin and are involved in so-called neurogenic inflammation. These neuropeptides are also thought to exert various functions within the immune system and act as nutrients and cytokines.

Thus, the central and peripheral nervous systems play a major role in the functioning of NS. For example, it is noted that more than 80% of epidermal Langerhans cells have connections with cutaneous nerve axons. The autonomic nerve connection with the intestine is also widespread. Neurons secrete a number of neuronal mediators including vasoactive intestinal peptides, somatostatin, calcitonin gene-related peptides, substance p, neurotensin, catecholamines, endorphins and cyclic nucleotides. In addition, receptors are generally found on cell surface membranes for serotonin, acetylcholine, and other neurotransmitters. Some of these neuromediators have been shown to modulate inflammation and other properties and activities in human skin and mucous membranes (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3; Non-patent document 4)
Skin symptoms or dermatological disorders afflict millions of people every day. These skin symptoms can be acute symptoms (which last only minutes or hours) or chronic symptoms that afflict individuals for days, months, years or lifetimes. There are a number of different dermatological symptoms that can be fungal, bacterial, or viral, or non-infectious immune reactions such as inflammatory reactions with or without allergic components. May or may be idiopathic. Symptoms may therefore be uneven, ranging from mild itching, redness and swelling to severe pustules and open ulcers, and in certain cases, debilitating manifestations such as degenerative ulceration May even cause. Regardless of the cause or specific symptoms, dermatological disorders can greatly affect an individual's quality of life. Examples of various diseases include atopy, psoriasis, contact dermatitis, acne, cancer, vasculitis and traumatic processes such as surgery, lacerations, burns, and infections, each of which And can adversely affect its appearance.

  Despite known and demonstrable connections and interrelationships between the human nervous system and mucus skin system, there has been little progress in the treatment of skin and mucosal wounds, scars and other diseases, disorders, and trauma . In general, typical treatments still rely on archaic techniques with limited utility and efficacy such as primarily debridements, sutures and oral and topical antibiotics.

  Therefore, new methodologies are needed that take advantage of and exploit the interrelationships between the nervous and mucus skin systems in the treatment of skin and mucosal diseases, disorders and trauma.

  Although society has made tremendous progress in the pharmaceutical field, there are naturally obstacles to the administration of any drug. In some cases, the disadvantages characterized as “side effects” can be so severe that a particular drug cannot be administered at a therapeutically effective dose. In such cases, medication is discontinued and other drugs may be tried. However, many drugs in the same treatment class show similar side effect profiles, meaning that the patient must either forgo the therapy or suffer from unpleasant side effects associated with a particular drug.

  Due to the spread of neurodegenerative diseases, skin damage, scars and other diseases, disorders and trauma of the skin and mucous membranes, as well as their devastating effects on patients, patient families and society in general and lack of effective and available treatments There is a strong demand for new and innovative approaches to their treatment and remission. Accordingly, there is interest in developing new methods and compositions for treating such diseases and conditions. In addition, combination treatments can be used to reduce the dose of individual components in the resulting combination while at the same time preventing unwanted or harmful side effects of the individual components. Thus, combined treatments and medications for the treatment of neurodegenerative diseases, skin damage, scars and other diseases, disorders and trauma of skin and mucosa resulting in reduced toxicity, reduced side effects, and increased therapeutic efficacy It is necessary to find an appropriate method including a strategy.

British Journal of Dermatology, 137 (6), 845-850, Dec. 1997 / L. Misery Journal of Investigative Dermatology, 127: 4/2007, Yannick Chateau, "In Vitro Reconstruction of Neuro-Epidential Connections" British Journal of Dermatology, 155 (5), 876-882, 2006 / Sancero, “Role of Neuropeptides in Psoriasis” Archives of Dermatological Research, 259: 3 / Jan. 2007 / Frosch, N.M. , “Synthesis of Prostaglandins in Psoriatic Skin”

The present invention relates to novel pharmaceutical compositions and methods for the treatment of various conditions, disorders, and diseases, and more particularly, one or more phosphodiesterase-5 inhibitors (PI-5). It relates to the treatment of such conditions, disorders, and diseases using therapeutic agents contained in combination with other agents.

  In certain embodiments, the present invention also provides a phosphodiesterase-5 inhibitor with one or more additional agents, such as a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), Any suitable to increase the chemical concentration of other neurotransmitters such as cholinesterase inhibitors (CI), dopamine agonists (DI) or amino acids, monoamines, neuropeptides and other drugs capable of primary neurotransmission in the synaptic cleft Also characterized is a pharmaceutical composition containing in combination with a novel agent (OI).

  In certain embodiments, the pharmaceutical composition comprises one or more PI-5 and one or more additional agents, such as a selective serotonin reuptake inhibitor (SSRI), a serotonin-noradrenaline reuptake inhibitor ( Increase chemical concentrations of other neurotransmitters such as SNRI), cholinesterase inhibitors (CI), dopamine agonists (DI) or amino acids, monoamines, neuropeptides and other drugs capable of primary neurotransmission in the synaptic cleft It may be contained in combination with any suitable drug (OI).

  In certain embodiments, the present invention provides a phosphodiesterase-5 inhibitor (PI-5) as one or more selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), cholinesterase inhibitors. Any suitable agent that increases the chemical concentration of other neurotransmitters (CI), dopamine agonist (DI) or amino acids, monoamines, neuropeptides and other agents capable of primary neurotransmission in the synaptic cleft ( OI) in combination with a novel composition for treating neurodegenerative diseases in a subject.

  In certain embodiments, the composition for treating a neurodegenerative disease comprises PI-5 selected from Cialis, LeVitra and Viagra.

  In a particular embodiment, the composition for treating a neurodegenerative disease comprises an SSRI selected from Luvox, Prozac, Celexa, Zoloft and Paxil.

  In certain embodiments, the composition for treating a neurodegenerative disease comprises a SNRI selected from Effexor and Cymbalta.

  In certain embodiments, the composition for treating a neurodegenerative disease comprises a CI agent selected from Cognex and Alicept.

  In certain embodiments, the composition for treating a neurodegenerative disease comprises DI selected from bromocriptine, Sinemet and Mirapex.

  In certain embodiments, compositions for treating neurodegenerative diseases increase chemical concentrations of other neurotransmitters such as amino acids, monoamines, neuropeptides and other agents capable of primary neurotransmission in the synaptic cleft. Any suitable drug (OI).

  In certain aspects of the invention, the OI is epinephrine, norepinephrine, dopamine, serotonin, melatonin, glutamic acid, gamma aminobutyric acid, aspartic acid, glycine, adenosine, ATP, GTP, vasopressin, somatostatin, neurotensin, leuteinizing hormone, insulin, Histamine, nitric oxide, carbon monoxide, acetylcholine, octopamine, tyramine, gastrin, cholecystokinin, oxytocin, neurophysin I, neurophysin II, neuropeptide Y, pancreatic polypeptide, peptide YY, corticotropin, Dynorphin, endorphin, enkephalin, secretin, motilin, glucagon, vasoactive intestinal peptide, growth hormone releasing factor, Yurokinin A, neurokinin B, substance P, bombesin, can be a gastrin releasing peptide or anandamide.

  In certain embodiments, combination drugs for treating neurodegenerative diseases are administered individually.

  In certain embodiments, a combination agent for treating a neurodegenerative disease is in a combined form such as a weekly patch, a monthly patch, a long-term injection, a combination pill, or an implant.

  In certain embodiments, the present invention provides PI-5 to at least one or more selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), cholinesterase inhibitors (CI), dopamine. In combination with an agonist (DI) or any suitable agent (OI) that increases the chemical concentration of other neurotransmitters such as amino acids, monoamines, neuropeptides and other agents capable of primary neurotransmission in the synaptic cleft It relates to a method for treating a neurodegenerative disease in a subject comprising administering to the subject a composition containing.

  In certain embodiments, the method for treating a neurodegenerative disease comprises administering the agents separately.

  In certain embodiments, a method for treating a neurodegenerative disease comprises administering an agent in a combined form.

  In certain embodiments of the invention, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia with Parkinsonian features, progressive supranuclear palsy Is essential dyskinesia or dementia.

  In a particular embodiment of the invention, the neurodegenerative disease is Alzheimer's disease.

  In a particular embodiment of the invention, the neurodegenerative disease is Parkinson's disease.

  In certain embodiments of the invention, the neurodegenerative disease is multiple sclerosis.

  In certain aspects of the invention, the neurodegenerative disease is amyotrophic lateral sclerosis.

  In certain embodiments of the invention, the neurodegenerative disease is frontotemporal dementia with Parkinsonian features.

  In certain embodiments of the invention, the neurodegenerative disease is progressive supranuclear paralysis, essential dyskinesia, or dementia.

  In a particular embodiment of the invention, the neurodegenerative disease is essential dyskinesia or dementia.

  In a particular embodiment of the invention, the neurodegenerative disease is dementia.

  In certain embodiments, the invention relates to the use of PI-5 in the manufacture of a medicament for treating a neurodegenerative disease, wherein the composition comprises at least one or more selective serotonin reuptake inhibitors (SSRIs), serotonin. Other neurotransmitters such as norepinephrine reuptake inhibitors (SNRI), cholinesterase inhibitors (CI), dopamine agonists (DI) or other drugs capable of primary neurotransmission in amino acids, monoamines, neuropeptides and synaptic clefts Further included is any suitable agent (OI) that increases the chemical concentration of.

  In certain embodiments, the present invention relates to a kit, the kit comprising PI-5 and one or more SSRIs, SNRIs, CIs, DIs or amino acids, monoamines, neuropeptides, and synaptic gaps in separate and discrete dosage forms. Packaged combinations with any suitable agent (OI) that increases the chemical concentration of other neurotransmitters, such as other agents capable of primary neurotransmission, and instructions for their use.

  In certain embodiments, the present invention relates to a method for treating neurodegenerative dementia (NDD) in a subject, wherein the method comprises phosphodiesterase-5 inhibitor (PI-5) and one or more selective serotonin reactivations. Administering to the subject a composition comprising an uptake inhibitor (SSRI) or a cholinesterase inhibitor (CI) in combination.

  In a particular aspect of this embodiment, the combination includes PI-5, SSRI, and CI, such as Cialis, Luvox and Cognex.

  In a particular aspect of this embodiment, Cialis is administered at a dose ranging from 20 mg to 100 mg / day.

  In a particular aspect of this embodiment, Luvox is administered at a dose ranging from 25 mg to 400 mg / day.

  In a particular aspect of this embodiment, Cognex is administered at a dose ranging from 10 mg to 160 mg / day.

  In certain embodiments, the invention relates to the use of a phosphodiesterase-5 inhibitor (PI-5) in the manufacture of a medicament for treating neurodegenerative dementia (NDD) in a subject, the composition comprising: Contains one or more: selective serotonin reuptake inhibitors (SSRI) or cholinesterase inhibitors (CI).

  In certain embodiments, the present invention relates to novel compositions and methods for improving the appearance and health of normal skin and mucous membranes and / or for promoting and accelerating healing of damaged skin and mucous membranes. .

  In certain embodiments, the present invention provides damage in a subject comprising a phosphodiesterase-5 inhibitor (PI-5) in combination with one or more selective serotonin reuptake inhibitors (SSRI) or cholinesterase inhibitors (CI). The present invention relates to a novel composition for treating received skin.

  In certain embodiments, the novel composition for treating skin damage comprises PI-5 selected from Cialis, LeVitra and Viagra.

  In certain embodiments, the novel composition for treating skin damage comprises at least one or more SSRIs selected from Luvox, Prozac, Celexa, Zoloft and Paxil.

  In certain embodiments, the novel composition for treating skin damage comprises at least one CI selected from Cognex and Alicept.

  In certain embodiments, the agents for treating skin damage are administered individually.

  In certain embodiments, the agent for treating skin damage is in a combined form such as a weekly patch, a monthly patch, a long-term injection, a combination pill, or an implant.

  In certain embodiments, the present invention relates to a method for treating skin damage in a subject, wherein the method comprises PI-5 at least one or more selective serotonin reuptake inhibitors (SSRI) or cholinesterase inhibitors (CI). And administering to the subject a composition comprising in combination.

  In certain embodiments, the method for treating skin damage comprises administering the agents separately.

  In certain embodiments of the invention, the skin injury is atopy, psoriasis, contact dermatitis, acne, cancer, or vasculitis.

  In certain embodiments of the invention, the skin injury is psoriasis.

  In a particular embodiment of the invention, the skin injury is contact dermatitis.

  In certain embodiments of the invention, the skin injury is acne.

  In certain embodiments of the invention, the skin injury is cancer.

  In a particular embodiment of the invention, the skin injury is vasculitis.

  In certain embodiments of the invention, the skin damage is the result of a traumatic process.

  In certain embodiments of the invention, the traumatic process is surgery, laceration, burns, or infection.

  In certain embodiments of the invention, the traumatic process is surgery.

  In certain embodiments of the invention, the traumatic process is a laceration.

  In certain embodiments of the invention, the traumatic process is a burn.

  In certain embodiments of the invention, the traumatic process is an infectious disease.

  In certain embodiments, the invention relates to the use of PI-5 in the manufacture of a medicament for treating skin damage in a subject, wherein the composition comprises at least one or more selective serotonin reuptake inhibitors (SSRIs). In addition.

  In certain embodiments, the present invention relates to a kit comprising a packaged combination of PI-5 in discrete and separate dosage forms and one or more SSRIs or CIs and instructions for their use.

  In certain embodiments, the present invention relates to a method for treating skin damage in a subject, wherein the method comprises phosphodiesterase-5 inhibitor (PI-5) with one or more selective serotonin reuptake inhibitors ( Administering to the subject a composition comprising a combination of SSRI) or a cholinesterase inhibitor (CI).

  In a particular aspect of this embodiment, PI-5 is Cialis, SSRI is Luvox, and CI is Cognex.

  In a particular aspect of this embodiment, Cialis is administered at a dose ranging from 5 mg to 80 mg / day.

  In a particular aspect of this embodiment, Luvox is administered at a dose ranging from 12.5 mg to 400 mg / day.

  In a particular aspect of this embodiment, Cognex is administered at a dose ranging from 5 mg to 60 mg / day.

  In certain embodiments, the invention relates to the use of a phosphodiesterase-5 inhibitor (PI-5) in the manufacture of a medicament for treating skin damage, wherein the composition comprises one or more selective serotonin reuptake inhibitors. (SSRI) or cholinesterase inhibitor (CI).

  While not wishing to be bound by theory, in a particular aspect of this embodiment, PI-5 is Cialis, SSRI is Luvox, and CI is Cognex.

  While not wishing to be bound by theory, in certain embodiments, the present invention acts to increase synaptic levels of nitric oxide and then both directly and indirectly to soluble guanylate cyclase. Relates to the administration of PI-5 inhibitors which act on to increase the formation of cyclic GMP.

  Without wishing to be bound by theory, in certain embodiments, the present invention relates to administration of a PI-5 inhibitor in combination with CI, which acts to increase the level of synaptic acetylcholine. .

  While not wishing to be bound by theory, in certain embodiments, the present invention relates to administration of a PI-5 inhibitor in combination with an SSRI that acts to increase the level of synapse serotonin. .

  In another aspect, the present invention provides a PI-5 inhibitor and one that directly or indirectly reduces undesirable side effects resulting from administration of this first agent or other additionally administered agent. A step of administering in combination with the above drugs.

  In another aspect, the present invention combines a phosphodiesterase-5 inhibitor (PI-5) with one or more other agents to increase neurotransmission in areas of the brain where the respective neurotransmitter functions. It relates to novel methodologies and systems for pharmaceutical combinations for the treatment of neurodegenerative diseases by administration.

  In one embodiment, the present invention, in one embodiment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia with Parkinsonian features, progressive supranuclear palsy, essential It features novel therapies for treating dyskinesia and neurodegenerative diseases such as dementia.

  In another aspect, the present invention provides for the promotion and acceleration of wound, burn and scar healing by administering a phosphodiesterase-5 inhibitor (PI-5) in combination with one or more SSRIs or CIs. It relates to novel methodologies and systems for pharmaceutical combinations for maintaining and improving skin and mucous membrane health.

  The present invention, in one embodiment, any that can adversely affect the body appearance such as atopy, psoriasis, contact dermatitis, acne, cancer, vasculitis or surgery, laceration, scar, burn, or infection It features a novel therapy for treating traumatic processes.

  In certain embodiments, the invention features a method of treating a subject with a phosphodiesterase-5 inhibitor.

  In certain embodiments, the treatment plan includes, for example, periodic monitoring of relevant physiological functions, including blood tests for liver function, kidney, and electrolytes, and / or physical tests, including EKG and treadmill tests. .

2 shows an exemplary time series flow chart for administering and monitoring the use of the treatment of the present invention.

(Detailed description of the invention)
Before describing the present invention in detail, unless otherwise indicated, the present invention is not limited to a particular formulation, active and inactive agent, mode of administration, or method of treatment or use; Need to be understood. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Scientific publications, patents or patent applications cited in various sections of this document are incorporated herein by reference for all purposes.

Definitions and terminology:
As used in this specification and the appended claims, the singular forms “a (a), (an)” and “the (the)” refer to plural referents unless the context clearly indicates otherwise. It should be noted that Thus, for example, "an active agent" means not only a single active agent, but also a combination of two or more different active agents, and "a dosage form" This means not only the above dosage forms but also combinations of dosage forms, and so on. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can also be useful in the practice and testing of the present invention, the preferred methods and materials are described below. Specific terminology that is particularly important for the description of the invention is defined below.

  When referring to an active agent, Applicants believe that the term “active agent” is not only the entity of the designated molecule, but also salts, esters, amides, prodrugs, conjugates, active metabolites, and other such entities. It is intended to include pharmaceutically acceptable and pharmacologically active analogs including, but not limited to, such derivatives, analogs, and related compounds.

  The terms “treating” and “treatment” as used herein refer to reducing the severity and / or frequency of symptoms, removing symptoms and / or underlying causes, and ameliorating or repairing damage. In certain embodiments, the terms “treating” and “treatment” as used herein refer to prevention of the occurrence of symptoms and / or causes underlying those symptoms. Thus, as used herein, “treating” a patient includes Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia with Parkinsonian features Treatment of neurodegenerative diseases such as progressive supranuclear palsy, essential dyskinesia or dementia. In other embodiments, “treating” a patient as used herein refers to skin diseases such as, for example, atopy, psoriasis, contact dermatitis, acne, cancer, vasculitis or skin or mucosal Accelerated and accelerated healing of wounds, burns and scars, such as dermatological disorders or trauma or any traumatic process such as surgery, lacerations, scars, burns, infections or any disease or condition that causes skin damage, Or it includes the maintenance and improvement of skin and mucous membrane health.

  The terms “effective amount” and “therapeutically effective amount” of an agent, compound, drug, composition or combination of the invention are non-toxic when administered to a subject or patient (eg, a human subject or patient) and any desired It is an amount effective to bring about a therapeutic effect.

  The term “dosage form” means any form of a pharmaceutical composition containing an amount of the active agent sufficient to achieve a therapeutic effect by a single administration. When the formulation is a tablet or capsule, the dosage form is usually just such a tablet or capsule. The frequency of administration that effectively yields the most effective results without overdose depends on the properties of the particular active agent, including the pharmacological properties of the active agent and its physical properties such as hydrophilicity. included.

  “Controlled release” means a drug-containing formulation or fraction thereof where drug release is not immediate, ie, using a “controlled release” formulation, administration does not result in immediate release of the drug into the absorption pool . This term is described in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995) is used interchangeably with “non-immediate release”. In general, the term “controlled release” as used herein includes sustained release and delayed release formulations.

  The term “sustained release” (synonymous with “sustained release”) is used in its conventional sense to provide for the slow release of a drug over a long period of time, preferably, although not necessarily, over a long period of time. By drug formulation results in a substantially constant blood level of the drug. The term “delayed release” is also used in the conventional sense to mean a drug formulation that, following administration to a patient, results in a measurable time delay before the drug is released from the formulation into the patient.

  “Pharmaceutically acceptable” means a material that is not biologically or otherwise harmful, ie, the material can be incorporated into a pharmaceutical composition that is administered to a patient, and is not desirable. It does not cause biological effects or adversely interact with other components of the composition containing the material. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, the carrier or excipient meets or meets toxicological and manufacturing test requirements. Is recorded in the Inactive Ingredient Guide created by the US Food and Drug Administration. A “pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, has the same type and degree of pharmacological activity as the parent compound. Refers to a derivative or analog. The term “pharmaceutically acceptable salt” includes, for example, acid addition salts formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid and the like. It is. Salts formed by free carboxyl groups are also derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, etc. Can be done.

Active drug combination:
The present invention relates to novel pharmaceutical compositions and methods for the treatment of various symptoms, disorders, or diseases, and more specifically, phosphodiesterase-5 inhibitors (PI-5) and one or more agents. It relates to the treatment of such symptoms, disorders or diseases using a therapeutic agent comprising in combination. In certain embodiments, PI-5 is an inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), cholinesterase inhibitor (CI), dopamine agonist (DI) with at least one or more selective serotonin reuptake. Or administered in combination with any suitable agent (OI) that increases the chemical concentration of other neurotransmitters, such as amino acids, monoamines, neuropeptides and other agents capable of primary neurotransmission in the synaptic cleft.

  The composition of the present invention may be administered to a patient for pharmaceutical treatment of a neurodegenerative disease. For example, the present invention includes Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia with Parkinsonian features, progressive supranuclear palsy, essential dyskinesia and dementia Prepare for neurodegenerative diseases such as The present invention includes treating a subject with PI-5 in combination with one or more SSRIs, SNRIs, CIs, DIs or OIs.

  Accordingly, the present invention relates to nerves by administering a combination of PI-5 and one or more agents that include, without limitation, SSRI, SNRI, CI, NI, DI, or OI that increase the target neurotransmitter. It relates to novel methods and compositions for the treatment of degenerative diseases. By combining these drugs according to the present invention, each reduces the side effects of other drugs, both contributing to the pharmacological efficacy for treating neurodegenerative diseases. Accordingly, the present invention relates to neurodegenerative diseases by administering a combination of PI-5 and one or more agents that include SSRI, SNRI, CI, NI, DI or OI that increase target neurotransmitters without limitation. The present invention relates to novel methods and compositions for the treatment of

  Furthermore, the compositions of the present invention may be administered to patients to improve the appearance and health of normal skin and mucous membranes and to promote or accelerate the healing of damaged skin. For example, the present invention treats a variety of diseases (traumatic processes such as atopy, psoriasis, contact dermatitis, acne, cancer, vasculitis or surgery that adversely affects the body appearance, lacerations, burns or infections) The present invention includes treating a subject with PI-5 in combination with one or more SSRIs or CIs.

  Thus, the present invention further provides for promoting and accelerating wound, burn and scar healing and maintaining and improving skin and mucosal health by administering a combination of PI-5 and one or more agents. Each of the drugs modulates the activity of the peripheral and central nervous system, particularly at the level of the percutaneous nerve, which in turn regulates various neuropeptides and nerves by the percutaneous and autonomic nerves. This results in the modulation of hormone secretion and activity, and these agents include without limitation SSRI or CI.

  Essentially all neurotransmission in both the central and peripheral nervous systems requires two chemical agents. The first agents are conventional or major neurotransmitter entities, of which more than 50 (including serotonin, acetylcholine, dopamine and norepinephrine) have been identified and described. Each of these conventional neurotransmitters has a relatively finite localization of function and neuroanatomy in the human nervous system. Acetylcholine is known to be the dominant conventional neurotransmitter in the neocortex and cortex, for example. The same is true for dopamine / dopa in the basal ganglia, substantia nigra and striatum pathway; serotonin in brainstem, reticular and raphe nuclei; and norepinephrine in brainstem and locus coeruleus. Acetylcholine and serotonin are known to play important functional roles in the peripheral nerve skin system.

  A second agent for effective neurotransmission is nitric oxide / cyclic-GMP (c-GMP), which appears to be preserved in the same manner throughout all formations and aspects of the human nervous system. This co-modulator or co-transmitter appears to interact with conventional neurotransmitters at the level of efferent neuronal cell membranes, possibly via glyco-lipo-protein cell receptors. Further effects may occur at intracellular or synaptic levels, possibly via gate channels, specific enzyme targets, microfilament sequences and cytokines.

  Defects primarily responsible for the vast array of neurodegenerative diseases and disorders are not always clear, and in fact can vary. However, whatever the mechanism, the cumulative effect is to inhibit effective neurotransmission, which is an essential function of the human nervous system, and the subsequent cascade system.

  While not wishing to be bound by theory, the present invention, in certain embodiments, is one chemical that increases c-GMP levels in targeted neuronal synapses and circuitry, and conventional in the same location. In combination with a second chemical that increases the level of neurotransmitter (s). Due to mass action or dynamic effects, the result is to overcome blunted and / or ineffective effective neurotransmission and subsequent cascades, regardless of the original location or cause of the neurodegenerative process. In this way, non-functional neurotransmission and secondary cascades are essentially disabled and function at a higher and more normal level of responsiveness. This reactivation of a nonfunctional neurotransmitter actually causes changes in neuronal plasticity, regeneration and apoptosis.

  Any agent, including currently available agents, suitable for increasing the synaptic concentration of these conventional neurotransmitters and c-GMP may be used in combination with PI-5 in the present invention.

  For example, autopsy changes seen in patients with advanced dementia represent the ultimate common pathway of initially reversible dysfunction in the cortex and neocortex, the cognitive regions of the human brain, and Combinations have been shown to cause “neural repair” of neuronal synaptic defects in these areas (and also in the reticular and raphe nuclei in the case of neurodegenerative dementia that is not associated with Parkinson's disease).

  PI-5 acts to increase the level of nitric oxide in the synapse, resulting in activation of soluble guanylate cyclase in the synapse and thus an increase in second messenger cyclic-GMP. CI acts to increase the level of acetylcholine, a monoamine neurotransmitter in the synapse. SSRIs act to increase the level of serotonin, another monoamine neurotransmitter in the synapse.

  The resulting increased cyclic-GMP acts in conjunction with acetylcholine on the efferent neuronal receptor protein to precisely modulate the activity of the receptor. This precise adjustment corrects defective neuronal synaptic activation, primarily in the cortex and neocortex, and may cause neuronal regeneration and plasticity.

  Increased cyclic-GMP also coordinates serotonin receptor activity in the reticulated complex and raphe nucleus in conjunction with serotonin. The modified neuronal synaptic activation in this area is then passed to the cortex and neocortex.

  While not wishing to be bound by theory, in another embodiment, the present invention itself relates to a pharmaceutical composition and / or treatment regimen comprising the administration of three agents, wherein the three agents are of serotonin. An agent that increases the synaptic concentration, an agent that increases the synaptic concentration of acetylcholine, and an agent that increases the synaptic concentration of cyclic-GMP.

  “Phosphodiesterase-5 inhibitor (PI-5)” means a substance or compound that inhibits (eg, prevents or reduces) the catalytic activity of the phosphodiesterase isoenzyme (P-5). Enzyme P-5 catalyzes the degradation of cyclic guanosine monophosphate (cGMP), a smooth muscle relaxant. Typically, an inhibitor is a small molecule (eg, less than about MW MW) that binds to the enzyme at the active site of the enzyme or at another site and prevents the normal activity of the enzyme. The bond may be a covalent bond, an ionic bond, or a bond through a hydrogen bond, or a combination thereof, and may be reversible or irreversible.

  One skilled in the art will appreciate that there are many compounds that are PI-5 inhibitors. Examples include, but are not limited to, sildenafil (Viagra), vardenafil (LeVitra), tadalafil (Cialis), zaprinast and the like. In one embodiment of the invention, the PI-5 used in the practice of the invention is sildenafil. In another embodiment of the invention, PI-5 is vardanefil. In yet another embodiment, PI-5 is tadalafil.

  In certain aspects of the invention, the composition may comprise one or more PI-5, eg, two PI-5s, three PI-5s, and so on.

  In certain embodiments of the invention, PI-5 is administered in combination with at least one selective serotonin reuptake inhibitor (SSRI). SSRIs affect the chemicals that nerves use in the brain to send messages to each other. These chemical messengers, called neurotransmitters, are released by one nerve and taken up by other nerves. Neurotransmitters that are not taken up by other nerves are taken up by the same nerve that released them. This process is called “recapture”. SSRIs work by inhibiting serotonin reuptake, an action that makes many serotonin available to be taken up by other nerves.

  SSRIs that can be administered in combination with PI-5 in accordance with the present invention include, but are not limited to: paroxetine (Paxil), fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), Cloboxamine, Ecitalopram, Femoxetine, Fresinoxane, Fluvoxamine (Luvox), Trazodone, Dimerzine, Ecitalopram (Lexapro), Alaprocrate, Nefazodone (Serozone), Dapoxetine, minlopramine, p , Indaprine, alaprolcrate, cericlamine, ifoxetine, torazo hydrochloride (Desyrel), venlafaxine, imipramine, imipramine N-oxide, desipramine, pirandamine, dazepinyl, nefopam, befuralin, fezolamine, cyanoimipramine, ritoxetine, cericamine, ceproxetine, WY 27866, WY 27866, imeldinabin , YM 922, S 33005, F 98214-TA, OPC 14523, alaprochlorate, cyanodotepine, trimipramine, quinupramine, dothiepine, amoxapine, nitroxazepine, McN 5652, McN 5707, VN 2222, L 792339, roxindol, YM 3599 6582, Org 6997, Org 6906, Amitripty , Amitriptyline N-oxide, nortriptyline, CL 255.663, pyrindole, indatraline, LY 113.821, LY 214.281, CGP 6085 A, RU 25.591, napamezol, diclofensin, EMD 68.843, BMY 42.568, NS 2389, Cerchloremin, Nitroquipazine, Ademethionine, Sibutramine, Cloboxamine and those described in US Pat. No. 6,365,633; and WO 01/27060.

  In a particular embodiment, the SSRI is Luvox. In other embodiments, the SSRI is Prozac. In another embodiment, the SSRI is Celexa. In another embodiment, the SSRI is Zoloft. In yet another embodiment, the SSRI is Paxil.

  In certain aspects of the invention, the composition may include one or more SSRIs, eg, two SSRIs, three SSRIs, and so on.

  In certain embodiments of the invention, PI-5 is administered in combination with at least a serotonin-norepinephrine reuptake inhibitor (SNRI). SNRI prevents selective uptake of the neurotransmitters norepinephrine and serotonin, but has no effect on the neurotransmitter dopamine.

  Suitable SNRIs that can be used in the present invention include atomoxetine, reboxetine venlafaxine (Effexor XR or Effexor), duloxetine (Cymbalta), desvenlafaxine (Pristiq), sibutramine (Meridia, Reductil), nefazoe (S) Includes, but is not limited to, milnacipran (Dalcipran or Ixel), and desipramine (Norpramine or Pertoflaneis).

  In certain embodiments, the SNRI is Effexor. In other embodiments, the SSRI is Cymbalta.

  In certain aspects of the invention, the composition may include one or more SNRIs, eg, two SNRIs, three SNRIs, and so on.

  In certain embodiments of the invention, PI-5 is administered in combination with at least a cholinesterase inhibitor (CI). A “cholinesterase inhibitor” is a compound that inhibits or reduces the activity of acetylcholinesterase or butyrylcholinesterase. CIs that can be administered in combination with PI-5 in accordance with the present invention include, but are not limited to: tacrine (Cognex), donepezil (Alicept), rivastigmine (Exelon) galantamine (Reminyl), hydrochloric acid Donepezil, metrifonate, physostigmine, huperzine A, physostigmine, heptylphyzostigmine, phenserine, torserine, simserin, thiatruthelin, distigmine bromide, thiasimerin, neostigmine, dichlorvos, phenethylnorsimserine, ganstigmine, cystytigmine , Edrophonium, TAK-147 (ie 3- [1- (phenylmethyl) -4-piperidinyl) -1- (2,3,4,5-tetrahydro-1H-1-benzazepine --8- yl) -1-propanone fumarate or other salts), T-82, Apureajin like.

  In certain embodiments, the CI is Cognex. In other embodiments, the CI is Alicept.

  In certain aspects of the invention, the composition may include one or more CIs, eg, two CIs, three CIs, and so on.

  In certain embodiments of the invention, PI-5 is administered in combination with at least any suitable agent that increases the level of effective dopamine at the appropriate neural synapse. In accordance with the present invention, dopamine agonists that can be administered in combination with PI-5 include, but are not limited to: bromocriptine (Parlodel), carbidopa / levodopa (Sinemet), pramipexole (Mirapex), cabergoline ( Dostinex), pergolide (Permax), rotigotine (Neupro), apomorphine (Apokyn), ropinirole hydrochloride (Requip), testosterone, cocaine, strychnine, memantine, Alicept, amantadine, lisuride, ER-230, doplexin, dopridel Sferamin, romergoline, carmoxylol, zelandopam, sumanilol, sibenadeto, quinpirole, kineloran, ta Pekisoru, roxindole, 4-alkylamino -2 (3H) - indolone compounds, SKF38393, SKF83959, SKF81297, SKF77434, SKF75670, SKF82958, dihydrexidine, Jinapusorin, A-77636, ABT-431, CY208-243, and A-68930.

  In certain embodiments, DI is bromocriptine. In other embodiments, DI is Sinemet. In another embodiment, DI is Mirapex.

  In certain aspects of the invention, the composition may include one or more DIs, eg, two DIs, three DIs, and so on.

  In certain aspects of the invention, PI-5 is at least any suitable agent that increases the chemical concentration of other neurotransmitters such as amino acids, monoamines, neuropeptides and other agents capable of primary neurotransmission in the synaptic cleft. Administered in combination with other drugs (OI). Suitable OIs that may be administered in combination with PI-5 according to the present invention include, but are not limited to: epinephrine, norepinephrine, dopamine, serotonin, melatonin, glutamic acid, gamma aminobutyric acid, aspartic acid Glycine, adenosine, ATP, GTP, vasopressin, somatostatin, neurotensin, luteinizing hormone, insulin, histamine, nitric oxide, carbon monoxide, acetylcholine, octopamine, tyramine, gastrin, cholecystokinin, oxytocin, neurophysin I , Neurophysin II, neuropeptide Y, pancreatic polypeptide, peptide YY, corticotropin, dynorphin, endorphin, enkephalin, secretin, motilin, glucagon, vasoactive intestine Peptides, growth hormone releasing factor, neurokinin A, neurokinin B, substance P, bombesin, gastrin releasing peptide, and anandamide.

  In certain aspects of the invention, the composition may include one or more OIs, such as two OIs, three OIs, and so on.

  In certain embodiments, the composition of the invention comprises one PI-5, one SSRI, and one CI.

  In certain embodiments, the composition of the invention comprises one PI-5, one SSRI, one CI, and one DI.

  In addition, by combining drugs according to the present invention, each reduces the side effects of other drugs and both contribute to the pharmacological efficacy for treating neurodegenerative diseases. In other embodiments, combining agents in accordance with the present invention may reduce the side effects of one agent present only in one other agent or two other agents or subject compositions. In another embodiment, the side effects of a single drug can be reduced as a result of the drug combination.

  Accordingly, the present invention relates to neurodegeneration by administering PI-5 in combination with one or more agents that include SSRI, SNRI, CI, NI, DI, or OI that increase target neurotransmitters without limitation. It relates to novel methods and compositions for the treatment of diseases and skin damage.

Dosage, formulation and administration:
Combination of PI-5 with one or more drugs that increase target neurotransmitters, including without limitation SSRI, SNRI, CI, NI, DI or OI, results in increased therapeutic effects and reduced side effects Thus, these pharmaceutical combinations make it an extremely effective treatment for the treatment of neurodegenerative diseases and the promotion and acceleration of wound, burn and scar healing, as well as the maintenance and improvement of skin and mucous membrane health. The therapeutic level of the combined drug varies from individual to individual and from disease to disease. A combination of PI-5 and a conventional neurotransmitter augmentation agent in an appropriate amount and interval effective for the treatment of any particular neurodegenerative disease inevitably is clinically performed by a home doctor, physician or neurologist. Monitored both chemically and chemically. Relevant formulations may ultimately take the form of daily combination pills, daily or weekly patches, long-term injections, implants, or short-acting forms of the drug.

  The selection of an appropriate dose for the drug used in the combination therapy according to the present invention can be determined and optimized by one of ordinary skill in the art, for example, by observation of the patient including the patient's overall health, response to the combination therapy, and the like. For example, if it is determined that a patient is not showing the desired therapeutic effect, or conversely, that the patient is experiencing undesirable or harmful side effects that are too numerous or serious in severity Would be necessary.

  In one embodiment, each component of the combination (eg, PI-5 and one or more SSRIs, SNRIs, CIs, NIs, DIs, or OIs) is generally prescribed for each component as a monotherapy. Formulated at a dose less than the prescribed dose. The components may be formulated separately or may be formulated as a combined dose. In one embodiment, each component of the combination (eg, PI-5 and one or more SSRIs, SNRIs, CIs, NIs, DIs, or OIs) is generally prescribed for each component as a monotherapy. Formulated at a dose less than the prescribed dose. In another embodiment, each component of the combination (eg, PI-5 and one or more SSRIs, SNRIs, CIs, NIs, DIs, or OIs) is generally prescribed for each component as monotherapy. It is prescribed at a dose that exceeds the dose that is given. The components may be formulated separately or may be formulated as a combined dose.

  In another embodiment, the prescribed dose of PI-5 exceeds the dose generally prescribed for monotherapy, and one or more of the SSRI, SNRI, CI, NI, DI, or OI is a single dose. Formulated below the generally prescribed dose for therapy. In another embodiment, the prescribed dose of PI-5 is less than or equal to the dose generally prescribed for monotherapy, and one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs are for monotherapy Is formulated at a dosage above that generally prescribed. In certain embodiments, a prescribed dose of PI-5 and one or more prescribed doses of SSRI, SNRI, CI, NI, DI or OI are each commonly prescribed for each component as monotherapy It is prescribed higher or lower than the dose.

  In certain embodiments, PI-5 can be administered, for example, 2 to 400 mg per day, including 2 to 200, and 2 to 100 mg per day. In one embodiment, PI-5 can be administered from 2 to 85 mg per day, including 2 to 80, 5 to 80, 10 to 80, and 5 to 70 mg per day.

  In certain embodiments, when Cialis is PI-5, Cialis can be administered, for example, 2-120 mg per day, including 4-70 mg per day. In one embodiment, Cialis is administered 5-60 mg per day.

  In certain embodiments, when LeVitra is PI-5, LeVitra can be administered, for example, 2-100 mg per day, including 4-90 mg per day. In one embodiment, LeVitra is administered 5-80 mg per day.

  In certain embodiments, when Viagra is PI-5, Viagra can be administered, for example, 5-400 mg per day, including 7.5-250 mg per day. In one embodiment, Viagra is administered 10-200 mg per day.

  In certain embodiments, the SSRI can be administered, for example, 5-600 mg per day, including 5-400, 10-400, 25-400 mg per day. In one embodiment, the SSRI is administered from 5 to 200 mg per day, including 50 to 200, 10 to 80, 10 to 50, 10 to 20 mg per day.

  In certain embodiments, when Luvox is an SSRI, Luvox can be administered, for example, 5 to 600 mg per day. In one embodiment, Luvox is administered 10-400 mg per day.

  In certain embodiments, when Prozac is an SSRI, Prozac can be administered, for example, 5-200 mg per day. In one embodiment, Prozac is administered 10-80 mg per day.

  In certain embodiments, when Celexa is an SSRI, Celexa can be administered, for example, 5-100 mg per day. In one embodiment, Celexa is administered 10-20 mg per day.

  In certain embodiments, when Zoloft is an SSRI, Zoloft can be administered, for example, 25-400 mg per day. In one embodiment, Zoloft is administered at 50-200 mg per day.

  In certain embodiments, when Paxil is an SSRI, Paxil can be administered, for example, 5-200 mg per day. In one embodiment, Paxil is administered 10-80 mg per day.

  In certain embodiments, the SNRI can be administered, for example, 5-500 mg per day, including 5-300, and 7-250 mg per day. In one embodiment, the SNRI is administered 20-200 mg per day.

  In certain embodiments, when the Effexor is an SNRI, the Effexor can be administered, for example, 5 to 500 mg per day. In one embodiment, Effexor is administered 10-400 mg per day and includes 25-300 and 50-200 mg per day.

  In certain embodiments, when Cymbalta is an SNRI, Cymbalta can be administered, for example, 10-400 mg per day. In one embodiment, Cymbalta is administered 20-200 mg per day.

  In certain embodiments, CI can be administered, for example, 5-200 mg per day, including 10-200, and 10-120. In one embodiment, CI is administered 5-120 per day and includes 10-120, 5-100 mg. In another embodiment, the SSRI is administered 10-20 mg per day.

  In certain embodiments, when Cognex is CI, Cognex can be administered, for example, 5-200 mg per day. In one embodiment, Cognex is administered 10-120 mg per day.

  In certain embodiments, when Alicept is CI, Alicept can be administered, for example, 5-100 mg per day. In one embodiment, Aricept is administered 10-20 mg per day.

  In certain embodiments, DI can be administered, for example, 0.125-80 mg per day, including 0.125-40. In another embodiment, DI is administered at 0.125-9 mg per day.

  In certain embodiments, when bromocriptine is DI, bromocriptine can be administered, for example, 2.5-80 mg per day. In one embodiment, bromocriptine is administered 2.5-20 mg per day.

  In certain embodiments, when Sinemet (25/100) is DI, Sinemet can be administered, for example, from 2 to 40 tablets per day. In one embodiment, Sinemet is administered from 2 to 40 tablets per day.

  In certain embodiments, when Mirapex is DI, Mirapex can be administered, for example, 0.125-40 mg per day. In one embodiment, Mirapex is administered at 0.125-9 mg per day.

  In certain embodiments, any suitable agent that increases the chemical concentration of other neurotransmitters, such as amino acids, monoamines, neuropeptides, and other agents capable of primary neurotransmission in the synaptic cleft is Be administered.

  In addition, patients can receive specific doses over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, etc.

  In some embodiments, an “effective amount” of a combination therapy is an amount that results in a decrease in at least one pathological parameter associated with a neurodegenerative disease or skin injury. Thus, for example, in some embodiments, an effective amount of a combination therapy is at least about 10%, compared to a reduction in expected parameters when using a single agent regime or no treatment at all, At least about 15%, at least about 20%, or at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60% An effective amount to achieve a reduction of at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or about 95%.

  When administered in separate formulations, PI-5 and one or more SSRIs, SNRIs, CIs, NIs, DIs, or OIs are substantially simultaneously (eg, within about 60 minutes, within about 50 minutes of each other, About 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 1 minute) or about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 10 hours , About 12 hours, about 24 hours, about 36 hours, or about 72 hours, or more apart.

  It is especially advantageous to formulate the compositions of the present invention in unit dosage form for ease of administration and uniformity of dosage. The specifications of the novel unit dosage forms of the present invention are based on the unique properties of compositions containing PI-5 with one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs and the specific therapeutic effects to be achieved. Dependent. The dose can be further determined by reference to the usual doses and modes of administration of the components. Formulating a single physically separate dosage form with each of the active ingredients of the combination treatment (eg, a single dosage form having PI-5 with one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs) It is also within the scope of the present invention.

  The method of administration of the composition or combination of the invention will depend in particular on the type of PI-5 used and one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs selected. PI-5 and one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs may be administered together in the same composition or simultaneously or sequentially in two separate compositions. Also, one or more PI-5s or one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs may be administered in the form of a therapeutic composition or in combination, for example, one administered simultaneously or sequentially. These may be administered to a subject or patient in the form of a separate composition. The schedule of administration will depend on the type of PI-5 and SSRI, SNRI, CI, NI, DI or OI chosen. For example, one or more PI-5s and one or more SSRIs, SNRIs, CIs, NIs, DIs or OIs may have a stimulating effect, the degree of such stimulating effect being determined by the particular drug selected Can vary depending on. Thus, one or more of PI-5, SSRI, SNRI, CI, NI, DI or OI may have a significant stimulatory effect, and thus have a less stimulating effect PI-5, SSRI, SNRI, CI , NI, DI or OI may be administered prior to that on the same day of administration. Similarly, one or more of PI-5, SSRI, SNRI, CI, NI, DI or OI may have a sedative effect, and the degree of such sedative effect may vary depending on the drug chosen. . Thus, one or more of PI-5, SSRI, SNRI, CI, NI, DI or OI having a significant sedative effect may be administered later than that of the same day of administration of a drug with less sedative effect. unknown. In addition, one or more of PI-5, SSRI, SNRI, CI, NI, DI or OI, each having less stimulating or sedative effects, may be administered simultaneously.

  Administration of the active agent can be performed using any suitable mode of administration. Thus, administration can be, for example, oral, topical, parenteral, transdermal, transmucosal (including rectal, vaginal, and transurethral), sublingual, by inhalation, or implanted in a dosage form It can be via a reservoir. The term “parenteral” as used herein is intended to include subcutaneous, intravenous, and intramuscular injection.

  Depending on the intended mode of administration, the pharmaceutical formulation is preferably in unit dosage form suitable for single administration of precise doses, e.g. tablets, capsules, caplets, liquids, suspensions, emulsions, suppositories, It can be solid, semi-solid or liquid such as granules, pellets, beads, powders. Suitable pharmaceutical compositions and dosage forms are known and relevant text and literature to those skilled in the art of pharmaceutical formulation such as Remington: The Science and Practice of Pharmacy (Easton, PA: Mack Publishing Publishing Co.). , 1995) and can be prepared using conventional methods. For orally active compounds, oral dosage forms are generally preferred and include tablets, capsules, caplets, solutions, suspensions and syrups, which can also include multiple granules, beads, powders, or pellets. May or may not be encapsulated. Preferred oral dosage forms are tablets and capsules.

  As noted above, it is particularly advantageous to formulate the compositions of the present invention in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form” as used herein refers to a physically discrete unit suitable as a unit dose for the individual being treated. That is, the composition is in separate dosage units, each containing a predetermined “unit dose” amount of active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. To be prescribed. The specification of the unit dosage form of the present invention depends on the specific properties of the active agent to be delivered. The dose can be further determined with reference to the usual dosages and modes of administration of the components. In some cases, two or more individual dosage units combined provide a therapeutically effective amount of the active agent, eg, two or more tablets or capsules taken together are in each tablet or capsule It should be noted that a therapeutically effective amount of PI-5 and SSRI, SNRI, CI, NI, DI, or OI selected such that a unit dose of approximately 50% of the therapeutically effective amount can be provided.

  Tablets can be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to the active agent, tablets generally contain an inert pharmaceutically acceptable carrier material such as a binder, lubricant, disintegrant, bulking agent, stabilizer, surfactant, colorant, and the like.

  Capsules are also preferred oral dosage forms for orally active pharmaceutically active agents, where the active agent-containing composition is in liquid or solid form (including particles such as granules, beads, powders or pellets). Can be encapsulated. Suitable capsules may be hard or soft and are generally made of gelatin, starch, or cellulose materials, with gelatin capsules being preferred. The two-piece hard gelatin capsule is preferably sealed using, for example, a gelatin band or the like. See, for example, Remington: The Science and Practice of Pharmacy, previously cited herein, which describes materials and methods for preparing encapsulated drugs.

  Whether it is a tablet, capsule, caplet, or particle, the oral dosage form provides for controlled release of selected PI-5 and SSRI, SNRI, CI, NI, DI or OI, if desired. In preferred embodiments, the formulations of the present invention are controlled release oral dosage forms. In general, these dosage forms provide for sustained release, ie, gradual release of PI-5 and SSRI, SNRI, CI, NI, DI or OI from the dosage form to the patient's body over time, Prepare for a substantially constant blood concentration of the drug over a range of about 4 to about 12 hours, generally about 6 to about 10 hours. In a particularly preferred embodiment, after oral administration of a dosage form containing PI-5 and SSRI, SNRI, CI, NI, DI or OI, peak blood levels are not reached until at least 4-6 hours have passed, There is a very gradual increase in the blood level of the drug such that the rate of increase of the level drug is approximately linear. In addition, in a preferred embodiment, there is an equally gradual decrease in blood levels at the end of the sustained release period.

  In general, as will be appreciated by those skilled in the art, sustained release dosage forms are obtained by dispersing an active agent within a matrix of a slowly hydrolyzable material, such as a hydrophilic polymer, or by an individual drug Formulations are made by coating containing dosage forms with such materials. Hydrophilic polymers useful for providing a sustained release coating or matrix include, for example, the following: hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, and sodium carboxymethylcellulose Cellulose polymers such as: acrylic acid polymers and copolymers preferably formed from acrylic acid, methacrylic acid, alkyl acrylate esters, methacrylic acid acrylic esters, etc., such as acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and Copolymer of ethyl methacrylate; and polyvinyl pyrrolidone, polyvinyl acetate, Vinyl polymers and copolymers such as vinyl acetate copolymer - and ethylene.

  A preferred sustained release dosage form herein is composed of acrylate and methacrylate copolymers commercially available from Rohm Pharma (Germany) under the trademark "Eudragit". Eudragit series E, L, S, RL, RS, and NE copolymers are available in aqueous dispersions or as dry powders, dissolved in organic solvents. Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as Eudragit L and Eudragit S series polymers. Particularly preferred such copolymers are Eudragit L-30D-55 and Eudragit L-100-55 (the latter copolymer is a spray-dried form of Eudragit L-30D-55 and can be reconstituted with water). The molecular weight of Eudragit L-30D-55 and Eudragit L-100-55 copolymers is about 135,000 Da and the ratio of free carboxyl groups to ester groups is about 1: 1. This copolymer is generally insoluble in aqueous liquids having a pH of less than 5.5. Another particularly suitable methacrylic acid-methyl methacrylate copolymer is Eudragit S-100, which is Eudragit L-30D-55 in that the ratio of free carboxyl groups to ester groups is about 1: 2. Different. Eudragit S-100 is insoluble below pH 5.5, but unlike Eudragit L-30D-55, it is poorly soluble in aqueous liquids having a pH in the range of 5.5-7.0. This copolymer is soluble at pH 7.0 and above. Eudragit L-100, which has a pH-dependent solubility profile between Eudragit L-30D-55 and Eudragit S-100, can also be used as long as it is insoluble at a pH below 6.0. it can. It will be appreciated by those skilled in the art that Eudragit L-30D-55, L-100-55, L-100, and S-100 can be replaced with other acceptable polymers having similar pH-dependent solubility characteristics. Will. Other preferred Eudragit polymers are cationic such as Eudragit E, RS, and RL series polymers. Eudragit E100 and EPO are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylate (eg, methyl methacrylate), whereas Eudragit RS and Eudragit RL polymers have a small proportion of neutral methacrylates. It is a similar polymer composed of trimethylammonioethyl methacrylate.

  Preparations for parenteral administration according to the invention include sterile aqueous and non-aqueous solutions, suspensions, and emulsions. Injectable aqueous solutions contain a water-soluble form of the active agent. Examples of non-aqueous solvents or vehicles include fatty oils such as olive oil and corn oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic properties such as polyethylene glycol Polymers, liposomes and the like are included. Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifying agents, dispersing agents, and stabilizing agents, and aqueous suspensions such as sodium carboxymethyl cellulose, sorbitol, and dextran. It may contain substances that increase the viscosity of the suspension. Injectable formulations are sterilized by incorporation of a sterilant, filtration through a bacteria retaining filter, irradiation, or heat. Injectable preparations can also be prepared using sterile injectable media. The active agent may also be in a dried, eg, lyophilized form, that can be reconstituted with an appropriate vehicle just prior to administration by injection.

  The active agent may also be administered through the skin using conventional transdermal drug delivery systems, and the active agent is contained within a laminate structure that serves as a drug delivery device that is applied to the skin. In such a structure, the drug composition is contained in a layer or “reservoir” under the top backing layer. The laminated structure may include a single reservoir or may include multiple reservoirs. In one embodiment, the reservoir may include a polymer matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Alternatively, the drug-containing reservoir and the skin contact adhesive may be present as separate and separate layers, the adhesive being under the reservoir, where the reservoir is in this case a polymer matrix as described above. Or it may be a liquid or hydrogel reservoir, or some other form of reservoir. The transdermal drug delivery system may further contain a skin permeation enhancer.

  In addition to the formulations described previously, the active agent can be formulated as a depot preparation for controlled release of the active agent, preferably for sustained release over a long period of time. These sustained release dosage forms are generally administered by implantation (eg, subcutaneously or intramuscularly, or by intramuscular injection).

  In another embodiment, the combination therapy of the present invention may be a topical formulation. In accordance with the present invention, an effective or optimal amount of a combination of PI-5 and SSRI, SNRI, CI, NI, DI or OI as a topical formulation is applied to the skin surface. As will be apparent to those skilled in the art, the effective or optimal amount will vary depending on the particular combination of agents used, the particular disease state or condition being treated, and the like. Topical formulations may be applied to any convenient local site. Local parts of interest include, but are not limited to, arms, legs, face, neck, torso and the like. Application can be accomplished in any convenient manner and is further directed at least in part by the form of the topical formulation. That is, whether a topical formulation exists as a cream, lotion, ointment, gel, solution, foam, powder or the like, depending on the container etc. containing the formulation. For example, the topical formulation may be sprayed onto the skin surface, rolled on the skin surface, or the subject may apply the topical formulation using a cotton swab, fingers, or the like. Other protocols for applying topical formulations are known to those skilled in the art and can be used according to the methods of the present invention.

  The compositions of the invention are generally administered orally, parenterally, transdermally, topically, or via an implanted depot, although other modes of administration are equally suitable. is there. For example, administration can be transmucosal, eg, transrectally or vaginally, preferably using a suppository containing an active agent plus an excipient such as a suppository wax. Transmucosal administration also includes transurethral administration, for example, as described in Place et al. US Pat. Nos. 5,242,391, 5,474,535, and 5,773,020. . Formulations for nasal or sublingual administration are also prepared using standard excipients well known in the art. The pharmaceutical compositions of the invention can also be formulated for inhalation, for example, as a solution in saline, as a dry powder, or as an aerosol.

Indications:
Neurodegenerative diseases While the present invention is useful in combination with many pharmaceuticals and therapeutic regimens, symptoms of particular interest include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's Frontotemporal dementia with clinical features, progressive supranuclear palsy, essential dyskinesia, and dementia.

  Combination of PI-5 with one or more drugs including, without limitation, SSRI, SNRI, CI, NI, DI or OI that increases the targeted neurotransmitter results in increased therapeutic effect and reduced adverse effects Particularly making these pharmaceutical combinations highly effective treatments in the treatment of neurodegenerative diseases. Subjects suitable for treatment with the combination therapy treatment regimen of the present invention include individuals suffering from the following symptoms associated with neurodegenerative diseases.

Parkinson's disease Parkinson's disease is a chronic and progressive neurodegenerative movement disorder that persists over time as symptoms continue to worsen. The disease was first reported by a London doctor named Dr. James Parkinson.

  Parkinson's disease is caused by gradual dysfunction and cell loss in the substantia nigra, the major dopamine producer in the brain. This neurotransmitter is thought to be responsible for sending information to different parts of the brain responsible for motor control and coordination. Reduced dopamine production delays the process of sending messages from the brain to various organs, disrupting the individual's ability to control and initiate any movement.

  Three important signs of Parkinson's disease are resting tremor (tremor), stiffness, and slowness at the start of exercise (called slow motion). Two of these features are required to make a diagnosis. Posture instability is the fourth important sign, which occurs late in the disease, usually more than 8 years after suffering from PD.

  A tremor at rest usually begins in one arm and may start and stop. Like most tremors, tremors worsen under stress and improve at rest or sleep. Months to years later, both arms may be affected, but the initial asymmetry (imbalance) is often maintained. PD tremor may also include the tongue, lips, or chin. There is a characteristic PD tremor and the extremities at rest are most prominent. Tremor may appear as a hand pill rounding motion or a simple hand or arm vibration.

  Robustness refers to an increase in resistance to someone else moving the patient's joint. The resistance is either smooth (lead tube like) or start and stop (gear like). (Gear-like is thought to be tremor, not strong.) Have someone else bend and stretch the patient's relaxed wrist and test for rigidity. Robustness can be made more apparent by voluntary movement of the opposite limb.

  Slow exercise refers to slowness of exercise, but also includes an unexpected decrease in exercise and a decrease in exercise size. Slow movement is also expressed as dwarfism (small handwriting), lack of facial expression (decreased facial expression), decreased blink rate, and dysphonia (soft speech).

  Posture instability refers to the imbalance and loss of reflexes used to keep the patient upright.

  This symptom is an important milestone because it is not easy to treat and is a common cause of disability late in the disease.

  Other symptoms include freezing at the start of walking (start 躊躇), freezing when changing direction, freezing when crossing a threshold, such as passing through the entrance, and bending of the neck, trunk, and extremities. Postural changes may occur, mental state changes commonly occur in late PD, and 15-30% of people with PD may be affected and short-term memory and visual spatial function may be impaired.

  The onset of PD is generally imbalanced, and the most common initial finding is asymmetric resting tremor in one arm. About 20% of people first experience awkwardness in one hand.

  The best clinical predictors of PD diagnosis are asymmetry, presence of resting tremor, and good response to dopamine exchange therapy.

  Parkinson's disease affects all people, regardless of their gender, economic status, geographical status, and social status. However, men have a slightly higher risk of developing this disease. In addition, some studies have also shown that white people are more susceptible to this disease than African Americans and Asians. Age is the ultimate determinant of the disease. As people age, they are more likely to develop this disease, but several cases of Parkinson's disease have been reported in people under 40 years of age.

Alzheimer's disease (AD)
Alzheimer's disease (AD), the most common cause of dementia, is usually a collection of brain diseases in the elderly, characterized by a gradual progressive loss of brain function, especially memory differences, disorientation, Confusion, mood swings, personality changes, language problems such as difficulty finding correct words about everyday things, loss of behavioral suppression, loss of motivation, and delusions are prominent. The prognosis and process of AD varies widely, and the duration of the disease can range from a few years to over 20 years. During this period, the part of the brain that controls memory and thought is affected first, followed by other brain changes that ultimately result in brain cell death.

  AD is characterized by distinct neuropathological changes in the brain. Among the most prominent are the emergence of neurofibrillar plaques and tangles in the cranial nerves that affect nerve synapses and nerve-nerve cell communication.

  AD primarily affects people over the age of 60. The risk of developing AD continues to increase with age. For example, people aged 80 have a significantly greater risk than people aged 65. About 5 million people in the United States and more than 30 million people worldwide have AD. Many of them have mild or minimal cognitive impairment, which often precedes dementia.

  Due to the aging of the population, the number of people with AD is expected to increase significantly over the next few decades. The disease affects all races and ethnic groups, and seems to have more women than men.

  AD is a progressive disease, meaning that the disease gets worse over time. The disease cannot be cured or reversed by any known treatment. Symptoms are often difficult to grasp at first.

  Over time, people with this disease lose their ability to make clear thoughts and inferences, situational judgments, problem solving, concentration, memorizing useful information, taking care of themselves, and even speaking, and changes in behavior and personality are common Is.

  People with mild AD typically require close monitoring and assistance with daily tasks such as cooking, shopping, and bill payments. People with heavy AD can do little by themselves and require full-time full care. For this reason, AD is considered a major public health problem. The cost of caring for people with this disease is estimated to be over $ 100 billion per year in the United States. The average annual cost per patient is between $ 20,000 and $ 40,000 depending on the severity of the disease. The cost does not take into account the loss of quality of life for the patient nor the physical and mental sacrifices of the home caregiver.

Amyotrophic lateral sclerosis (ALS)
ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease of upper and lower motor neurons located in the midbrain, brainstem, and spinal cord. In ALS, motor neurons in these areas become dysfunctional and slowly die, and when this occurs, the muscle can no longer receive nerve impulses from the brain. The muscles then weaken and shrink, resulting in muscle paralysis. ALS is characterized by a rapidly progressive degeneration of motor neurons in the brain and spinal cord, which ultimately leads to paralysis and premature death. Overall, the prevalence of ALS is low (about 5 per 100,000), but the incidence increases with age, peaks between 55 and 75 years, and progression of ALS patients is fairly rapid Only 5% of ALS patients survive 5 years after diagnosis. Diagnosis of ALS is performed by a neurologist and generally follows a series of signs and symptoms, but does not follow the normal clinical course and does not show any typical signs and symptoms of conventional ALS There are ALS cases.

  ALS can develop as weakness, awkwardness, or atrophy in one or more limbs. This may begin as difficulty swallowing or speaking. Symptoms can be overlooked at first and overlooked. Common symptoms include the following: difficulty standing, walking or running, awkwardness-frequent hand movements such as tripping or falling, buttoning, writing, unlocking locks Difficulty, hand muscle atrophy, tongue atrophy, food mastication difficulty, swallowing difficulty (dysphagia), speech difficulty, irritable laryngeal reflex, language formation difficulty (articulation disorder), weakness and atrophy in certain muscles, strained and stiff muscles (Spasticity), muscle spasms, and muscle twitches (fibrous bundle contractions) found under the skin.

  There may be evidence of frontal lobe dysfunction in patients with ALS. This dysfunction is usually asymptomatic (not easily visible or causes symptoms) and can only be detected when specifically looked for by focused testing. However, in a small number of patients, clinically significant cognitive impairment becomes apparent and is accompanied by a continuation that extends beyond frontotemporal dementia. In addition to difficulties in planning and sequencing (the most common manifestation of “executive dysfunction” due to frontal lobe disease), some patients may be inattentive or lack insight into the patient's own situation that cannot be explained by other methods, as well as the patient and patient May express their influence on loved ones and others, and fortunately rarely, patients may not be as friendly as their own patients. These aspects of ALS, if present, can pose a major challenge for caregivers and health care workers alike, and these aspects can be associated with shorter survival.

  Depression and anxiety may occur in patients with ALS. Although difficult to prove, such depression and anxiety may be part of the disease process itself rather than the patient's mere response to the patient's symptoms. Depression and anxiety can be treated. Ultimately, some patients with ALS exhibit so-called uncontrollable emotions that appear as an involuntary uncontrolled eruption of laughter or crying that is different from the underlying mood.

  As the disease progresses, people with ALS lose the ability to perform daily activities such as dressing, eating and working. Eventually, it will be impossible to get out of bed without assistance. The person becomes restricted to a wheelchair or bed (development of pressure ulcers can be a problem). As breathing muscles weaken, breathing becomes increasingly difficult. Increased risk of pneumonia.

  Each year about 5,000 people are diagnosed with ALS in the United States, and about 20,000 people are thought to have the symptoms. ALS affects all racial and ethnic groups. The disease can occur at any age but is most common in people aged 40-60 years. Men often take more than women. No treatment is available for ALS and the effects of this disease are not reversible.

Multiple sclerosis (MS)
Multiple sclerosis is a neurological disease of the central nervous system and can occur in young people as well as older people. Nerves in various parts of the brain are coated with protective insulators composed of protein myelin and other proteins embedded in the lipid sheath so that electrical impulses that cause nerve conduction are protected. In MS, inflammation and the presence of autoimmune antibodies to myelin and other antigens cause destruction of the protective sheath, losing their protective ability (demyelination), resulting in a decrease or loss of electrical impulses along the nerve Become. In progressive MS, neurons are damaged by unsheathing and plaque buildup on the neurons until neuronal cell death occurs.

  Signs and symptoms of MS include visual impairment, muscle weakness, fatigue, numbness, difficulty in coordinating exercise and balance, tremor, dizziness, hearing loss, memory loss, impaired judgment, behavioral changes and pain. These symptoms initially begin in a cycle or relapse-remission, become progressive later, and regression occurs steadily. MS affects virtually any myelinated, sensory or motor neuron and can cause a wide range of signs and symptoms.

  The symptoms of multiple sclerosis can vary from person to person. Visual, sensory, and motor signs and symptoms are all essential elements of multiple sclerosis. Clinical manifestations vary and there is therefore a wide range of symptoms that can appear. Some people have mild cases of multiple sclerosis with little or no disability over the years. Others have a more severe type of multiple sclerosis that requires restraint in a wheelchair or bed. Still other people may spend their entire life without symptoms (some people without multiple sclerosis symptoms may know by chance that there are multiple sclerosis lesions, or after death Some people have revealed that they were affected by this disease. This variability sometimes makes it difficult to diagnose multiple sclerosis. Signs and symptoms are often misunderstood as psychiatric in origin.

  Multiple sclerosis commonly affects the cerebellum, the part of the brain responsible for balance and fine motor coordination. As a result, people with multiple sclerosis often have difficulty maintaining their balance when walking and performing delicate tasks with their hands. Unexplained drops of cups or other items, or abnormal weakness can occur.

  Patients may experience facial pain, a sense of rotation called dizziness, and sometimes hearing loss. Virtually any area of the body can be involved, making the disease a great mimic of other disorders of the nervous system. Patients may experience painful muscle spasms or weakness in one or more of their arms or legs. Nerve fibers that convey pain sensations, tactile sensations, and temperature sensations are often affected, causing tingling, numbness, or electrical type pain in the chest, abdomen, arms, or legs.

  Multiple sclerosis may involve the nerves responsible for involuntary movements of the bladder and intestines. Patients often have constipation and urinary retention. These symptoms lead to other complications such as bladder, kidney, or blood infections.

  Most people with multiple sclerosis complain of constant fatigue. As simple as carrying groceries and climbing stairs, it can be an impossible task for people with multiple sclerosis.

  Multiple sclerosis is more common in Nordic people. Women are more than twice as likely to develop multiple sclerosis than men. Multiple sclerosis usually affects people aged 20-50 years, with an average age of onset of about 34 years.

Frontotemporal dementia (FTD)
The FTD is a group of heterogeneity of symptoms clinically defined by gradual and progressive changes in behavior and personal behavior and / or gradual and progressive language dysfunction. Initial symptoms generally occur without affecting other cognitive areas such as memory, and are rarely present at age of onset and above. In some instances, behavioral and language deficits are also associated with Parkinsonism or progressive motor neuron disease. Neuropathologically, FTD is caused by neurodegeneration in the frontal and / or temporal lobes.

  The most common manifestations are early changes in social and personal behavior, characterized by difficulty in adjusting behavior to the social demands of the situation. This is often associated with a lack of suppression, resulting in impulsive or inappropriate behavior such as inadequate predicate, frustration explosion or lack of social sensation.

  As the disease progresses, this can lead to overt criminal behavior (eg shoplifting), poor financial judgment, or impulsive shopping. In extreme cases, this impulsivity can be self-destructive, such as when a patient attempts to get off a moving car. Some people have inappropriate sexual behavior.

  There can also be repetitive or forced behavior. This may include engulfing repeated specific actions (eg, reading the same book many times) or repeating specific physical movements (eg, walking to the same location many times).

  Eating habits and personal cleanliness can also change. Overeating is as common as a temporary epidemic of food where only certain foods can be eaten. There is a loss of interest in the appearance of the person, and the patient may become increasingly undressed early in the disease process.

  All this occurs in the context of patients who show little insight or personal interest in their behavior. Even if there is a complaint for memory impairment, these patients do not have true amnestic syndrome. Those patients can keep track of the events of the day and can be adapted.

  FTD affects an estimated approximately 250,000 Americans, or the prevalence of FTD among people aged 45-64 was estimated at 6.7 per 100,000. The disease affects both sexes equally. About 40% of patients have a clear family history. The average duration of the disease is about 8 years.

Progressive supranuclear palsy (PSP)
Progressive supranuclear palsy is a rare degenerative disorder of the brain. This disease impairs exercise and balance. Many people with PSP also experience changes in mood, behavior, and personality. Degradation of cognitive mental processes such as thought, memory, attention, and speech is not uncommon. When these mental changes are severe enough to interfere with daily activities, they are called dementia.

  PSP is progressive, meaning that the PSP gets worse over time. The disease affects the part of the brain above the nucleus (“on the nucleus”), which is a pea-sized structure in the part of the nervous system that controls eye movements. Paralysis means weakness, and the disease is named after this characteristic weakness in eye movements.

  PSP symptoms usually appear very slowly. Many people experience long-term symptoms such as fatigue (feeling exhausted), headache, joint pain, dizziness, and depression. Gradually, the following more specific symptoms appear: unexplained balance problems, stiff or unsteady steps when walking, very slow movements, frequent falls, awkwardness, visual problems (looks blurry or doubled) , Eye movement control problems and eye contact cannot be maintained), photosensitivity, behavioral or personality changes, irritation, moodiness, memory loss, forgetfulness, lethargy (indifference), sluggish thinking, reasoning, planning, inappropriate Laughter or cry, anger or aggressive explosion, obscure speech, swallowing problems, masked facial expression (no expression), muscle spasms, and inability to urinate (incontinence).

  About 20,000 people in the United States have PSP. This disease usually develops in people over 60 years of age. The disease sometimes affects people in their 40s or 50s, but symptoms generally become prominent in the early 60s. PSP is slightly more common in men than in women.

  Because PSP primarily affects older people and has some similar symptoms, PSP is often mistaken for Parkinson's disease, a much more common movement disorder. The distinction is important. This is because treatments that help many people with Parkinson's disease do not help people with PSP.

Essential dyskinesia Dyskinesia is involuntary excessive abnormal movement. There are several different types of dyskinesia, each with different clinical symptoms, causes, and treatments. Adults and children with certain chronic brain disorders often show symptoms of dyskinesia. Movement can occur in the head, arms, legs, hands, feet, lips, or tongue. Dyskinesia can be classified as dance disease, dystonia, myoclonus, tremor, and late seizures (late onset type). Other forms of dyskinesia include athetosis, balism, akathisia, tics, stereotypies, and Musums legs. Dyskinesia can also be called hyperkinetic syndrome.

  Chorea is an abnormal movement that is an irregular, involuntary, nonrhymic, sudden, rapid, non-persistent jerking movement that flows continuously from one part of the body to another. The exercise is cut off, in a short time, and rarely occurs. Dance illnesses can make persistent contractions impossible, causing the affected person to drop things. People with dance illness have irregular dance-like steps. The cause of dance disease is not completely understood.

  Dystonia that occurs at rest can remain as a (clonic) form of exercise. Dystonia is either localized or systemic. Focal dystonia is an involuntary movement in a single body part, which typically includes blepharospasm (upper face), spastic torticollis (neck), and writer's cramp. Dystonia that affects more than one body area is called segmented dystonia. Systemic dystonia commonly affects the trunk, one or both legs, and another body part. Other types of dystonia include Merge syndrome (jaw muscle spasms when opening and closing mouth). Spastic dystonia can cause speech problems due to convulsions of the laryngeal (throat) muscles. The intensity of muscle exercise in patients with dystonia can vary, and symptoms worsen during fatigue, stress, activity, and posture changes. In some cases, the strange symptoms of dystonia can be mistaken for a psychological illness. Dystonia can be inherited or acquired for another temporary cause. Inherited diseases that exhibit dystonia are rare and include dopa-responsive dystonia, idiopathic tension dystonia, and x-linked dystonia-parkinsonism (found among Ashkenazi Jews).

  Myoclonus refers to short, sudden, severe muscle contractions (positive myoclonus), and shock-like movement or inhibition (negative myoclonus). Myoclonus can be systemic or sequestering. Movement consists of rhythmic, irregular or oscillatory jerks that occur suddenly and then disappear. Abnormal convulsions are associated with environmental stimuli such as light, sound, movement, and visual threats. This symptom may be misdiagnosed as epilepsy. Myoclonus usually occurs at rest, but can also appear when the affected body part is subjected to voluntary activity, which is called active myoclonus. Make myoclonus inactive more incompetent than resting myoclonus.

  Tremor is a regular, rhythmic oscillatory movement that changes in speed, position, amplitude, and stationarity, and may depend on the type and severity of the tremor. Tremor can occur when active, resting, and maintaining position or posture. Tremor is so fast that it is often described as “blinking light”. Subtypes of tremor include resting tremor, postural tremor at rest or activity and inherited tremor, or tremor with movement (intentional “dynamic” tremor) Is included. Resting tremor is usually slow, occurs during activity, and disappears when action is initiated (eg, Parkinson's disease). Essential tremor is usually benign, but can cause disability due to writing disabilities and restriction of activities related to daily life. Essential tremor can be inherited.

  Paroxysmal dyskinesia is a group of disorders including paroxysmal exercise-induced dyskinesia, accidental ataxia, paroxysmal hypnotic dyskinesia, paroxysmal exertion-induced dyskinesia, and paroxysmal non-motor-induced dyskinesia. Paroxysmal dyskinesia is a hyperactivity disorder characterized by intermittent involuntary movements consisting of symptoms from other movement disorders such as dance disease, athetosis, dystonia, and balism. Episodic dyskinesia episodes can last from a few seconds to several days. Accidental ataxia is characterized by intermittent episodes of ataxia that can last from seconds to hours. Paroxysmal dyskinesia can be caused by prolonged exertion, sleep, stress, alcohol, coffee, tea, fatigue, sudden voluntary movements, heat, or cold.

  Athetosis is a movement disorder characterized by continuous, slow, and writhing movements. Movement is generally limbic and involves the muscles of the face, neck, and tongue frequently. This condition can occur at rest or when performing voluntary exercise. The speed of movement of an affected person can sometimes increase, and the symptoms are similar to those of dance disease (called choreoathetosis). If muscle contraction persists and causes an abnormal posture, athetosis exercise can be mixed with dystonia exercise.

  Valism is a large chorea that is fast and usually affects the limbs. Affected individuals show a movement that is thrown out and struck. In general, balism affects one side (unilateral) of the body, resulting in a condition called unilateral balism.

  Akathisia refers to complex movements such as tics, compulsions, and oddities that are stereotypic and are usually relieved by exercise. In general, when sitting, a person with akathisia may show movements that include symptoms such as crossing and unraveling, stroking, stiffening, stroking the scalp, or shaking the body . The patient may have a burning sensation in a particular affected body part, and the patient may make continuous moans and groans.

  Tick can be divided into two disorders: motor tic (abnormal movement) and / or voice tic (abnormal sound). Children may exhibit both motor and vocal tic chronic disorders (Gilles de la Tourette syndrome). Simple tic movements can be very similar to chorea of chorea or myoclonic (sudden, simple, sudden, isolated). Complex tics are well-tuned patterns of continuous movement, but they may not be the same from occurrence to occurrence and can occur in different body regions. The tic is a rapid movement, and if the contraction is sustained in the affected body part, the tic resembles a dystonia movement.

  One of the major clinical signs that help distinguish tics from other dyskinesias is the presence of involuntary eye movements in people with tics. Tic eye symptoms may include brief eye cramps or persistent eye diversion. Two other dyskinesias, myoclonus and dystonia, may show involuntary ocular symptoms. With voice tics, the affected person may make a crushing voice, coughing, or even an obscene language (stigma). Phonetic tics (with nasal and vocal cord muscles) can be divided into simple phonetic ticks such as coughing or nasal slipping or complex phonetic tics that include bellow-like noise and verbalization.

  Stereosis is an exercise that is frequent and can last for several minutes. These movements are repetitive and identical (continuous stereotypy). This strange movement associated with mental retardation, autism, and schizophrenia is stereotypy. Continuous stereotypy is characteristic of another type of dyskinesia called tardive dyskinesia resulting from treatment with neuroleptics and antipsychotics.

  Late (late onset) dyskinesia refers to a group of movement disorders characterized by hyperactive involuntary movements consisting of mixed symptoms of orofacial dyskinesia, dance disease, tics, and / or athetosis. Abnormal movement can affect the muscles of the lips, face, trunk, tongue, and extremities, which can be an obstacle to diet and dexterity. The most characteristic symptom of late-onset dyskinesia is orofacial dyskinesia, which usually begins with a slow and gentle tongue movement, followed by an exaggerated movement of the lips and tongue. Affected individuals may have symptoms that may progress to chewing movements, blinking, cheek swelling, frowning, arched eyebrows, and blepharospasm. Late onset dyskinesia is commonly seen in patients taking certain medications such as psycholeptics and antipsychotics prescribed for schizophrenia, schizophrenic affective disorder, or bipolar disorder. Other types of late dyskinesia include late-onset akathisia, late-onset dystonia, late-onset myoclonus, late-onset Tourette syndrome, late-onset tremor, and eyelid spasm. Approximately 50% of patients taking dopamine receptor blocker drugs develop a type of tardive dyskinesia. Late onset akathisia refers to repetitive tapping, moji-moji, and march. Exercise associated with tardive dystonia can include a fixed posture of the face, neck, trunk, and extremities. Persons with a rare disorder, delayed myoclonus, show brief jerking movements of the muscles of the face, neck, trunk, arms, and legs. Symptoms of late Tourette syndrome usually begin in people over 21 years of age and include frequent multiple tics of both voice and movement. This disorder should not be confused with Tourette's syndrome, which usually appears by the age of seven. Delayed tremor often manifests as an involuntary, rhythmic, wavy, continuous movement of the head, neck, limbs, or voice. Present in both delayed tremor, resting and voluntary movements.

  Early myoclonic encephalopathy is a rare disorder with an incidence of about 1 in 40,000 children. Early myoclonic encephalopathy is characterized by short, sudden myoclonic convulsions (common in 90% of patients) and seizures. The onset of symptoms usually occurs within the first 3 years of birth. Treatment and management depends on the underlying cause of the seizure. In general, patients receive antiepileptic drugs and improvement in symptoms is usually associated with a good prognosis. If symptoms are not improved by antiepileptic drug (s), prognosis is not good.

Dementia “Dementia” refers to a significant loss of cognitive function to the extent that behavior and quality of life are significantly affected. Dementia generally manifests as memory loss, decreased mathematical and analytical abilities, and impaired organization and effective function.

  Based on autopsy results, dementia is estimated to occur in 20-30 percent of the world population. Incidence in the United States is expected to increase significantly as our population ages. Dementia is often progressive and patients with dementia suffer from a significantly higher incidence of trauma, abuse, suicide and other serious illnesses. Dementia results in mental distress and financial difficulties for both patients and patient families.

  The most common causes of dementia are vascular disorders such as stroke (30-40 percent), neurodegenerative disorders such as Alzheimer's disease, multiple sclerosis and Parkinson's disease (25-40 percent), EtOH, liver Medical disorders such as insufficiency and hypoglycemia (20 percent), and occupied lesions such as brain tumors and subdural hematomas.

  There is essentially no effective treatment for neurodegenerative dementia. Several agents for the treatment of Alzheimer's disease are commercially available, such as Cognex and Alicept, but their effectiveness has been demonstrated to be minimal and non-persistent.

  Symptoms of dementia vary greatly depending on the person and the underlying cause of dementia. Most people affected by dementia have some (but not all) of these symptoms. These symptoms may be very obvious, or they may be very difficult to catch and remain unrecognized for some time. The first sign of dementia is usually a loss of short-term memory. Such a person repeats what he just said or forgets where he left the object just a few minutes ago.

  Other symptoms and signs of early dementia are as follows: speech dysfunction (may be compensated by using synonyms or defining words), name, appointment, or what the person did Forgetting things, getting rid of things, difficult to perform familiar tasks (driving, cooking food, housework, personal financial management), personality changes (for example, social people are withdrawn, quiet people are rough) And become silly), uncharacteristic behavior, mood swings (often accompanied by short-term anger or rage), poor judgment, behavioral disorders-delusions and suspicion, reduced functional levels (but at home) Can follow daily work), confused, unfamiliar in an unfamiliar environment (sometimes hesitating to return to a familiar place).

  Other symptoms and signs of medium-term dementia are as follows: worsening symptoms seen in early dementia, reduced ability to compensate, activities of daily life without help (eg bathing, dressing, grooming) Inability to eat, use toilets, sleep disruption (often snoozing during the day, waking up at night), unable to learn new information, increased disorientation and confusion even in a familiar environment, lack of judgment And increased risk of falls and accidents due to confusion, behavioral disturbances-paranoid paranoia, aggression, violence, inappropriate sexual behavior, hallucinations, storytelling (the person has done or experience never happened) Carelessness, poor concentration, loss of interest in the outside world, and abnormal mood (anxiety, depression).

Other symptoms and signs of severe dementia are as follows: worsening of symptoms seen in early and mid-term dementia, complete dependence on others for activities of daily life, walking from place to place without assistance Or other movement disorders such as swallowing that may make it impossible to move (increased risk of malnutrition, suffocation, and aspiration (aspiration of food and beverages, saliva, or mucus into the lungs), short-term and long-term Complete loss of memory (even familiar relatives and friends may become unrecognizable), complications-dehydration, nutritional problems, problems with bladder control, infection, aspiration, seizures, pressure ulcers, and trauma from accidents or falls May not be aware of these issues, especially behavioral issues. This is especially true later in dementia.

  Depression in the elderly can cause dementia-like symptoms. As many as 40% of people with dementia are also depressed. Common symptoms of depression include depressed mood, loss of interest in previously enjoyed activities, withdrawal from others, sleep disturbance, weight gain or loss, suicidal thoughts, worthless feelings, clearly thought or concentration Loss of ability to do.

  People with irreversible or untreated dementia show a slow and gradual decline in mental function and movement over the years. Complete dependence and death are the final stages, often due to infection.

  Dementia is most common in the elderly; it was once called aging and was considered a normal part of aging. Dementia is not a normal part of aging, but is caused by multiple underlying medical conditions that can occur in both older and younger people. In some cases, dementia can be reversed by appropriate medical treatment. In other cases, dementia is permanent and usually worsens over time.

  About 4-5 million people in the United States have some degree of dementia, and the number will increase over the coming decades as the population ages. Dementia affects about 1% of people aged 60-64 and 30-50% of people over the age of 85.

  Dementia is the number one reason for bringing older people into institutions such as nursing homes. Dementia is a very serious condition that results in significant financial and human costs. Many people with dementia eventually become completely dependent on others for their care. People with dementia generally remain fully conscious, but short-term and long-term memory loss is common.

  People with dementia use areas of intellectual function, such as language and number use; perceptions of what is happening around them; judgments; and inferences, problem solving, and abstract thinking Also experience a decline in all or any of the ability to These losses not only impair the ability of individuals to function independently, but also have a negative impact on quality of life and relationships.

  As pointed out above, the present invention increases the level of conventional neurotransmitter (s) at the same location with chemicals that increase c-GMP levels in targeted neural synapses and networks. It is a combination with the second chemical. Due to mass action or dynamic effects, the result is to overcome blunted and / or ineffective effective neurotransmission and subsequent cascades, regardless of the original location or cause of the neurodegenerative process. In this way, non-functional neurotransmission and secondary cascades are essentially disabled and function at a higher and more normal level of responsiveness. This reactivation of a nonfunctional neurotransmitter actually causes changes in neuronal plasticity, regeneration and apoptosis.

  For example, neurodegenerative dementia (for example, Alzheimer's disease and FTDP-12) can be treated with a combination of PI-5 and CI. This is because these chemicals target the cortex and neocortex where these diseases are thought to occur.

  Similarly, dyskinesia (examples are Parkinson's disease, Musm's leg syndrome and progressive supranuclear palsy) can be treated with a combination of PI-5 and DI. This is because these chemicals target the basal ganglia, substantia nigra and nigrostriatal pathways thought to cause these diseases.

  Neurodegeneration-related fatigue and bradydinesis / anergy / Anhedonia (examples are Parkinson's disease and sporadic neurofibrosis) can be treated using a combination of PI-5, SSRI, and NI. This is because these chemicals target the brainstem, reticular body and locus ceruleus, where these diseases are thought to occur.

  Central sleep apnea (narcolepsy is an example) can be treated using a combination of PI-5, SSRI and NI. Because these chemicals target the brainstem, reticulum, raphe nucleus, locus ceruleus and the ascending pathway from the reticulum to the substantia nigra and substantia nigra, which are thought to cause these diseases. Because.

  Amyotrophic lateral sclerosis and cranial neuropathy and medullary dysfunction can be treated using a combination of PI-5, SSRI, and NI. This is because these chemicals target the brain stem, raphe nucleus, locus ceruleus and cranial nerve nucleus where these diseases are thought to occur.

In addition, treatment of neurodegenerative dementia (NDD) can be treated using a combination of SSRI, CI and PI-5. For example, the optimal dose range may be as follows:
PI-5 (eg, Cialis) = 20 mg to 100 mg / day SSRI (eg, Luvox) = 25 mg to 400 mg / day CI (eg, Cognex) = 10 mg to 160 mg / day Should be individually dosed every 3 days during follow-up.

  Finally, as further clinical and laboratory data become available, other neurodegenerative diseases that should be described now and in the future target PI-5 and target neuroanatomically and functionally affected areas. Can be treated by combining conventional neurotransmitter (s) that are localized to the agent (s) that increase.

Promoting and accelerating healing of wounds, burns and scars and maintaining and improving skin and mucosal health In addition, the compositions of the present invention provide for promoting and accelerating the healing of wounds, burns and scars, and the health of skin and mucous membranes. Can be administered to patients for maintenance and improvement. For example, the present invention can be used to treat various diseases (atopy, psoriasis, contact dermatitis, acne, cancer, vasculitis) or traumatic processes (surgery, laceration, burns, infections) that adversely affect the body appearance. Prepare. The invention includes treating a subject with PI-5 in combination with one or more SSRIs or CIs. Some representative conditions are described in more detail below.

atopic:
Atopic or atopic dermatitis is a very common and often chronic (persistent) skin disease affecting a large proportion of the world population. This skin disease is also called eczema, dermatitis, or atopy. Most commonly, this can be considered a type of skin allergy or sensitivity. A triad of atopic dermatitis includes asthma, allergy (hay fever), and eczema. This disease has a known genetic component and is more common in some families. Characteristics of this disease include rash and itching.

  The term “dermatitis” means inflammation of the skin. “Atopic” refers to a disease that is inherited in a family and often occurs together. In atopic dermatitis, the skin becomes very itchy and inflamed, causing redness, swelling, cracking, exudation, crust formation, and scales. Dry skin is a very common complaint and is the root cause of some of the typical rash symptoms.

  Atopic dermatitis can occur at any age, but most often affects infants or young children. In some instances, atopic dermatitis may persist until adulthood or may actually appear for the first time later in life. Many patients tend to have a long course with various vertical movements. In most cases, the disease has a period called exacerbation or enlargement, followed by a period called remission in which the skin improves or is completely cured. Many children with atopic dermatitis enter permanent remission of the disease when they grow up, but their skin remains slightly dry and easily stimulated.

  Several factors can induce or exacerbate atopic dermatitis, including dry skin, seasonal allergies, exposure to tight soaps or detergents, new dermatological products or creams, and cold weather. Environmental factors can activate the symptoms of atopic dermatitis at any time in the life of a person who has inherited the traits of atopic disease.

psoriasis:
Psoriasis affects about 2-3% of the world population and about 7 million people in the United States. Psoriasis is a chronic inflammatory hyperproliferative disease of the skin characterized by well-defined, erythematous scaly plaques. Psoriasis can consist of one or two lesions or can be a wide range of skin diseases with incapacitated arthritis or desquamation. The exact pathogenesis of psoriasis remains uncertain, but there are several treatment options. For example, monoclonal antibodies have been used in attempts to combat psoriasis, but this treatment option is primarily used to treat systemic psoriasis, as opposed to localized infection. Since most psoriasis patients have only localized psoriasis, the mainstay of treatment remains the use of topical drugs.

  Topical steroids such as triamcinolone have been used for many years to treat psoriasis. While topical steroids are effective in the treatment of psoriasis, their use, if used extensively, is detrimental, such as those described above and systemic effects such as skin atopy or HPA-axis suppression May be related to adverse side effects.

Contact dermatitis:
Contact dermatitis is a localized rash or irritation of the skin caused by contact with a foreign body. Substances that cause contact dermatitis in many people include "toxic" plants such as poison ivy, certain foods, some metals, cleaning solutions, detergents, cosmetics, perfumes, industrial chemicals, and latex rubber.

  There are two types of contact dermatitis, allergic and irritating. Allergic contact dermatitis results from an immune system reaction. Thus, in allergic contact dermatitis, there is a skin reaction to something that touches the skin at that site. Unlike most allergic reactions, the trigger is external rather than internal. In contrast, irritant contact dermatitis results from contact with substances that directly damage human skin. Many chemicals, including industrial cleaning products, solvents, detergents, can cause this symptom.

Acne:
Acne appears when oil (sebum) glands stimulated by male hormones from the adrenal glands of both boys and girls become active around adolescence. Fat is a natural substance that oils and protects the skin, and under certain circumstances, cells near the surface block the sebaceous gland opening and cause the accumulation of fat below. This fat stimulates and grows bacteria (which inhabits any skin and generally does not cause any problems) and causes inflammation of surrounding tissues.

  If the inflammation is close to the surface, it becomes a pustules; deeper becomes papules (acne); deeper becomes cysts. If the fat appears on the surface, the result is a chalazion. If the fat is oxidized (ie, affected by oxygen in the air), the fat changes from white to black, and the result is a “black blister”.

Skin cancer:
Skin cancer is the most common of all human cancers. Some forms of skin cancer are diagnosed in more than 1 million people each year in the United States.

  Cancer occurs when normal cells undergo transformation, during which time normal cells grow and proliferate without normal control. As the cells grow, they form a mass called a tumor. Skin tumors are often called lesions.

  Only when the tumor is malignant is a cancer a tumor that erodes and invades neighboring tissues due to uncontrolled growth of the tumor. Tumors can also metastasize to distant organs through the bloodstream or lymphatic system. Tumors overwhelm the surrounding tissues by eroding the surrounding tissues and depriving them of the oxygen and nutrients they need to survive and function.

  There are three main types of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.

  The majority of skin cancers are BCC or SCC. While malignant, they are unlikely to spread to other parts of the body. They may locally impair the appearance if not treated early.

  A small but significant number of skin cancers are malignant melanoma. Malignant melanoma is a very aggressive cancer that tends to spread to other parts of the body. These cancers can be fatal if not treated early.

  Like many cancers, skin cancer begins as a precancerous lesion. These precancerous lesions are changes in the skin that are not cancer but can become cancer over time.

Vasculitis:
Vasculitis is a general term for a group of rare diseases characterized by vascular inflammation. The body's blood vessels are called the vasculature. Blood vessels are composed of arteries that carry oxygen-rich blood to body tissues and veins that carry oxygen exhausted from the tissues to the lungs for oxygen. Vasculitis is characterized by inflammation in and damage to various blood vessel walls.

  Each vasculitis disease is defined by a certain pattern of vascular involvement, specific organ involvement, and distribution of laboratory test abnormalities. As a group, these diseases are called vasculitis.

  The actual cause of these vasculitis diseases is usually unknown. However, vascular immune system abnormalities and inflammation are common features. Each form of vasculitis has a characteristic pattern of its own symptoms, many of which depend on which particular organ is affected.

  Examples of vasculitis include Kawasaki disease, Behcet's disease, polyarteritis nodosa, Wegener's granulomatosis, cryoglobulinemia, Takayasu arteritis, Churg-Strauss syndrome, giant cell arteritis (temporal arteritis) , And Henoch-Schönlein purpura.

Traumatic process (surgery, laceration, burn, infection)
Scar formation is a natural part of the healing process after trauma. Various factors such as the depth and size of the wound or incision and the location of the trauma affect how the skin leaves and heals. In addition, age, heredity, gender and ethnicity affect how a person's skin responds to wounds and scars.

  These are several different types of scars. Keloid scars are the result of an overly aggressive healing process. These scars extend beyond the original trauma. Over time, keloid scars can affect mobility. Possible treatments include surgical removal or steroid injection. Smaller keloids can be treated using cryosurgery (cryotherapy using liquid nitrogen). Once traumatic, keloid formation can be prevented by using a pressure treatment or a gel pad using silicone.

  Spastic scars result from skin burns that tighten the skin and impair its ability to move. In certain cases, this type of scar reaches deeper and affects muscles and nerves.

  A hypertrophic scar is created, a red scar that resembles a keloid but does not break the boundaries of the trauma site.

  The therapeutic levels of the three combined drugs vary from person to person and to disability. A combination of SSRI, CI and PI drugs in an appropriate amount and interval that is effective to treat any particular burn, scar, wound, disease or disorder of the mucus-skin system is inevitably Monitored both clinically and chemically by a physician, physician or neurologist. The formulation may ultimately take the form of a combination pill given daily, a daily or weekly patch, a long-term injection, or an implant.

Typical optimal dose ranges are as follows:
PI-5 (eg, Cialis) = 5 mg-80 mg / day SSRI (eg, Luvox) = 12.5 mg-400 mg / day CI (eg, Cognex) = 5 mg-60 mg / day In general, the optimal dose interval (oral formulation) is Is as follows:
SSRI = 1 × to 4 × / day PI = 1 × to 4 × / day CI = 1 × to 4 × / day Dosage starts at a low level and is dosed individually every 3 days at follow-up by the treating physician Should be set. To ensure maximum patient safety, monitoring should also include blood tests for liver and kidney function and electrolyte levels as per current standard treatment when administering individual drugs. In addition, a thorough physical examination, including EKG and possibly a treadmill examination, should be performed before the start of treatment. FIG. 1 shows a flowchart of the presented methodology. If nerve regeneration, replication and plasticity occur selectively and there is a chance of remission, rather than healing, it may be necessary to reduce the dose as usage continues.

  In each of the above examples, PI-5 acts to increase nitric oxide levels in the targeted synapse and increase second messenger c-GMP. The resulting increased c-GMP, in concert with related conventional neurotransmitters, acts on efferent neuronal receptor proteins and other structures to properly regulate receptor activity. This correct adjustment improves defective neuronal synaptic activation and may also result in neuronal regeneration and plasticity.

  The above discussion has focused on a small fraction of the potential mechanisms of action for the combination of the present invention, and the present invention itself is a pharmaceutical composition as well as one agent of c-GMP. Synaptic concentration (s) of conventional neurotransmitter (s) that are known to increase synaptic concentration and the other agent (s) act on the target region (s) of the human brain Relates to a treatment regimen consisting of administration of these two or more agents.

  To ensure maximum patient safety, monitoring should also include blood tests for liver and kidney function and electrolyte levels as per current standard treatment when administering individual drugs. In addition, a thorough physical examination, including EKG and possibly a treadmill examination, should be performed before the start of treatment. If nerve regeneration, replication and plasticity occur selectively and there is a chance of remission rather than cure, or if the disease is exacerbated, it may be necessary to modify the dose as usage increases. FIG. 1 shows a flowchart of the presented methodology. If nerve regeneration, replication and plasticity occur selectively and there is a chance of remission, rather than healing, it may be necessary to reduce the dose as usage continues.

  Regardless of the actual regimen chosen, the therapeutically effective level should not cause significant side effects, but should be at a level that minimizes symptoms of neurological impairment. In light of the current treatment plan situation, this level should begin to improve, but should not be the dose level at which the improvement reaches its peak and is maximized. This dosage may vary over time, but should primarily reflect changes in the patient's physical condition including, for example, distribution volume, kidney and liver function, body weight, and changes in the underlying disease.

kit:
Kits for performing the methods of the invention are also provided. The kits of the invention can vary greatly with regard to the components included. The kit of the present invention includes at least a combination of separate and distinct dosage forms of PI-5 with one or more SSRIs, SNRIs, CIs, DIs, or OIs and instructions for their use.

In certain embodiments, the kits of the invention can be used by patients to treat neurodegenerative diseases or to promote or facilitate wound, burn and scar healing, and to maintain and improve skin and mucosal health. Includes instructions for performing drug administration. The instructions may be recorded on a suitable recording medium or on a substrate. For example, the instructions may be printed on a substrate such as paper or plastic. Thus, the instructions may be present as a package insert in the kit, such as during the labeling of the kit's container or its components (ie, associated with a package or sub-package). In other embodiments, the instructions exist as electronic storage data files that reside on a suitable computer readable storage medium, such as a CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, eg, via the Internet. An example of this embodiment is a kit that includes a web address where instructions can be viewed and / or where instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate. To maintain sterility, some or all of the components of the kit of the invention are packaged in suitable packaging. May be. In many embodiments of the kit of the present invention, the kit components are packaged in a kit storage member to create a single easy-to-handle unit, and the kit storage member, eg, a box or similar structure, It may or may not be an airtight container to further preserve the sterility of some or all of the components of the kit. In certain embodiments, the kits of the invention comprise a sealed package of a controlled release dosage form, the dosage form comprising a separate discrete dosage form of PI-5 and one or more SSRIs, SNRIs, CIs, DIs, or Provides combination with OI and instructions for its use.

  The invention is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents and patent application publications cited throughout this application are hereby incorporated by reference.

Example 1
A 58-year-old white male with moderate NDD secondary to Parkinson's disease received a combination of PI-5, SSRI, and CI. The patient has been suffering from Parkinson's disease for about 12 years and has no significant complications. The patient weighed 210 pounds and had a body mass index (bmi) of 0.20. Patients have a moderate loss of apraxia, slowness of movement and short- and medium-term visual and audio memory combined with a decline in analytical, mathematical, creativity and organizational skills in the last 7 months. There was somatic progression with progression. Initial trials were performed for renal and liver function. Renal function test showed a creatinine level of 1.0 and liver function test (LFT), both within the normal range. Close-up tests as criteria for dementia include CBC, SMAC, UA, EKG, CXR, MRI brain (no gadolinium), syphilis test, AIDS test, pulse oximetry, sedimentation rate, thyroid function test and B-12 level Only an initial trial of L-Dopa (Sinemet) resulted in transient success and mild changes in stiffness and tremor, followed by mild deterioration. Another trial of Cognex and aspirin resulted in no change in dementia. After 4 weeks of the Luvox and Cialis dosing schedule shown in Table 1 below, a 20 percent improvement in the dementia evaluated was observed. After another week of the Luvox, Cialis and Cognex dosing schedules shown in Table 1 below, 95 percent improvement was observed in the dementia evaluated. This level of improvement was sustained without significant “on / off” for 10 months without significant clinical or chemical side effects.

上記は、選ばれた薬剤による効果的な用量を提供するが、半減期および他の特性の選択に応じて、同様の用量設定技術を用いて現行および将来のＳＳＲＩ、ＣＩおよびＰＩ−５薬剤と他の組み合わせをする場合は同等の用量を当業者が確立できるはずであることが理解されなければならない。

The above provides an effective dose with the selected drug, but with current and future SSRI, CI and PI-5 drugs using similar dose-setting techniques, depending on the choice of half-life and other properties. It should be understood that equivalent doses should be established by one skilled in the art for other combinations.

(Example 2)
The second subject was diagnosed with non-specific but rapidly progressing multisystem neurodegenerative disease at age 57. Clinical progression and further diagnostic findings suggest frontotemporal dementia with cortical medullary disease. Early symptoms were accompanied by idiopathic dementia and progressed rapidly over 3-4 months. Severe generalized myoclonus with high amplitude with ataxia, dyspahagia, central and peripheral dyspnea (CPAP required), dizziness, and hypokinetic stiffness continued for about a month and continued to progress as well as dementia.

  The patient had mild facial acne that had responded to topical and oral antibiotics for about 10 years, had vitiligo on the finger, and atrophic depigmentation of the left upper leg secondary to chemical burns 30 years ago. There was one missing 4 × 4 cm scar. There have been more than 10 years of mild intermittent gingival infections that require minimal surgical intervention due to degeneracy from the dentition.

The patient's work-up included the following findings:
1 / MRI brain x 2 (onset / 20 months later) no contrast-normal range 2 / SPECT (disease course 20 months) drug use-normal range 3 / sleep test (disease course 24 months) no drug use -Significantly abnormal with frequent central and peripheral hypopnea episodes, worsened to 80-90% oxygen saturation 4 / Alleles 4,5 positive for apolipoprotein e
Serum assay positive for 5 / KCNC3 mutant (major dominant locus determinant for ataxia) 6 / high homocysteine-25

  The patient was a non-smoker and did not take any alcohol or other drugs. The patient has concurrent chronic fibrillation, a chronic illness, that is currently rate controlled by exercise alone and intermittent anticoagulation with coumadin.

  There is a positive family history of a father who died at age 62 due to complications from a fall in a nursing home. There is no family history of cancer of major skin disorders. Both parents had multiple extractions with both gingival infections and carriers and required subsequent dentures. The father's diagnosis at that time was end-stage Parkinson's disease. Responses to multiple dopamine agonist regimens, cryosurgical resection of the lateral basal ganglia, were poor.

  Patients were initially treated individually with Sinemet, Cognex (cholinesterase inhibitor), Luvox (SSRI), Cialis and Viagra (phosphodiesterase 5 inhibitor), and what clinical response to neurological disease, skin and mucosal disorders There was not. However, the combination of a phosphodiesterase 5 inhibitor with either Cognex or Luvox or both resulted in dramatic improvements in all neurological symptoms and skin disorders. The mucosal decline that had separated from the native teeth was also improved. The patient's scars were not caused.

  When patients received oral combinations of phosphodiesterase 5 inhibitor, SSRI, and cholinesterase inhibitor, the greatest improvement in neurologic xally was observed in the mucocutaneous system. A 90% improvement in mucocutaneous disease was observed and maintained during the course of treatment. The effect of each drug was observed within 20 minutes in all parameters, and the maximum response was seen within 3 doses of each drug. When Cialis-5 mg oral TID, Cognex-10 mg oral TID, and Luvox-100 mg oral TID were used, an optimal combination with essentially no side effects was observed and maintained for 20 months. A 24 hour dose placed in a 7.5 cc aqueous solution was also applied topically to the previously mentioned scar. Ten percent scar regression was observed in one week, and 95% scar resolution and visually normal tissue replacement occurred in two months. Ekg, CBC, UA, LFT, renal function, calcium, TFT remained normal at disease onset and at 4 months follow-up with oral drugs. Rare dry mouth was observed with normal glucose. Occasional frontal pain was quickly alleviated by low dose oral Tylenol. Viagra is equally replaced with oral Cialis at a dose of 50 mg TID. Paxil is replaced equally with Luvox at a dose of 20 mg TID. Patients also take 1 mg of folic acid and vitamin B6 per day. Repeated attempts to discontinue chronic medication resulted in a recurrence of neurological and mucocutaneous abnormalities within 5 days.

(Example 3)
The third subject was diagnosed with atypical Parkinson's disease, the first onset was 15 years ago, with low-amplitude gear-like scattered tremor, diffuse muscle stiffness, mild motor slowness, and gait abnormalities . The patient also had severe seborrheic dermatitis and scarred facial acne rosacea for over 25 years, with minimal response to topical and oral antibiotics. All symptoms progressed slowly to the current state of high severity in all symptoms and signs. Important work-ups included the following:
1 / MRI brain (no contrast) x 2/3 years after onset, 15 years after onset-within normal range 2 / PET brain (isotope unknown / 10 years from disease)-Symmetry in the cortex (at this point) Further details are not available)
3 / paradoxical reaction with hypotension and worseness of rigidity and tremor.

  Patients are non-smokers, social drinkers, have minimal alcohol consumption and no history of drug abuse. Chronic borderline hypertension problems (treated with dietary restriction and Hytrin), benign prostatic hypertrophy (treated with Hytrin and vodting training), GERD for short-term treatment with Pepcid in addition to Prilosec, cervical spine and For DJD of the lumbar spine, treatment with physiophysical therapy, Tylenol and, if necessary, Vicoden.

  Patients were treated chronically with low-dose amantadine with little or no improvement in all symptoms. There was no change in seborrheic dermatitis or rosacea acne.

  Initially treated with Sinamet and Mirapex on two separate occasions, the patient showed mild deterioration for all neurological symptoms. Nine months ago, patients started treatment with a combination of Cialis (phosphodiesterase 5 inhibitor) and Luvox (SSRI) and a combination of Cognex (cholinesterase inhibitor) and amantadine. The improvement in neurological symptoms was subjectively observed by the patient at 20 minutes, with the greatest improvement after 3 doses. Without the phosphodiesterase 5 inhibitor, no improvement occurred using any of the drugs individually or any combination of the above drugs.

  On day 3, mild improvement of seborrheic dermatitis was observed, and on day 10, mild improvement of rosacea acne was observed. The following sequential doses maximally improved all neurological and mucocutaneous problems: Cognex-10 mg oral TID / Luvox-100 mg oral TID / Cialis-30 mg oral TID / others as before treatment.

  The patient maintained an 80% improvement in all symptoms during 9 months of treatment. Without antibiotic treatment, seborrheic dermatitis resolved 95% and rosacea acne resolved 80%. Baseline and every 4 months ekg, CBC, LFT, calcium, BUN, CXR remained normal. Occasional nausea occurred but resolved within a few hours with short-term treatment with Prilosec and Pepcid.

Example 4
A fourth subject was diagnosed with Parkinson's disease and received a combination of PI-5, SSRI, and DI. Initial symptoms were right hand asymmetric tremor and generalized stiffness. Slow progression over 20 years includes severe scattered gear-like stiffness, scattered pill rounding tremor, severe motor slowness with vocal symptom, inherent inability to move due to severe gait abnormalities, mask-like facial features The close inspection included the following:
1 / CT brain (no contrast / onset of disease)-within normal range 4 / carotid artery double (4 years ago)-within normal range 2 / MRI brain (no contrast / 10 years after disease)-within normal range 3 / TSH 6.5 was minimally elevated, but slowly increased to normal T3 / T4 4 / cholesterol 210, LDL160. Intermittent treatment with statin, reduced to 160 and 120 respectively.

  Patients smoke 15 packs of cigarettes per year, but not 20 years. I don't like alcohol at all and there is no illegal drug abuse. Medical problems include asthma, and mild cases are treated with inhaled B agonists only. Basal cell carcinoma of the right back was successfully excised locally with no recurrence.

  The patient continued to receive chronic Sinamet and initially had a very mild reaction.

  The patient later tried Mirapex and Bromocryptine for a short period of time with no significant changes. Six months ago, the patient started treatment with Luvox (SSRI), Cialis (phosphodiesterase 5 inhibitor) in addition to Sinamet. The first improvement was observed within 1 hour of taking all drugs, with the greatest improvement when taking 4 doses. As long as Cialis was not included, no change was observed with any combination of the above drugs.

  Maximum improvement, i.e. about 80 percent improvement in all symptoms) occurred in subsequent dosing schedules and persisted for 6 months. Luvox-1 daily 400 mg oral, 3 divided doses / Cialis-1 daily 20 mg oral, 3 divided doses / others as before. Note that Cognex (cholinesterase inhibitor) caused mild improvement in all symptoms when added to the above regimen, but was discontinued due to gastrointestinal upset.

  As above, there were no significant side effects and BC, creatinine / LFT / TSH / ekg / cxr / calcium were normal at baseline, 1 month of treatment, and 5 months of treatment. In addition, 80% resolution of chronic rosacea acne was observed.

(Example 5)
The fifth control was diagnosed with Alzheimer's disease and dementia and was administered a combination of PI-5, SSRI and CI. Initial presentation with short-term amnesia. Progression over 15 years has resulted in severe dementia with loss of short and medium term memory, executive functioning, decision making, etc. The patient was hospitalized in a nursing home for Alzheimer's and was indwelled due to incontinence for intermittent and recurrent lower urinary tract infections requiring intermittent lower urethral obstruction and chronic inhibitory antibiotics. A Foley catheter was used. Four years ago, a PEG feeding tube was installed due to nutritional problems and dysphagia.

Important past work-ups include:
1 / CT head (no IV contrast / 12 years ago)-within normal range 2 / carotid artery double (6 years ago)-mild, non-occlusive plaque R internal carotid artery 3 / lumbar puncture (4 years ago, febrile Confused)-Within normal range.

  The patient also did not smoke or abuse illegal drugs. The patient took a moderate amount of alcohol but did not reach about 34 years (no complications recorded).

  Patients were initially administered Cognex (a cholinesterase inhibitor) and later Alicept, but there were no significant clinical status changes. Seven months ago, the patient resumed taking Cognex in addition to Luvox (SSRI) and Cialis (phosphodiesterase 5 inhibitor). No significant changes were observed until 2 weeks after maximal treatment began. A mild improvement in all symptoms occurred over 6 weeks, reaching approximately 45 percent of baseline. The patient is currently continuing tube feeding but taking liquids and solids orally. In addition, the Foley catheter is interrupted.

  The patient still has moderate dementia, but short-term memory has improved. The patient speaks short monosyllable sentences and responds appropriately to verbal stimuli. Families take patients home and receive home nurse visits and physical therapy services.

  No improvement was observed with any single drug using any drug combination that did not contain a phosphodiesterase 5 inhibitor. Maximum improvement is maintained for 6 months with the following medications.

  Cognex-1 daily 90 mg, 3 divided doses / Luvox-1 daily 400 mg, 3 divided doses / Cialis-1 daily 20 mg, divided into 2 doses).

  No significant side effects have occurred and ekg, CBC, BUN, Cr, TSH, calcium, LFT remain in the normal range. During two weeks, Alicept was successfully replaced with Cognex without noticeable changes.

Equivalent:
Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and covered by the claims. Various substitutions, adjustments, and changes may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. Other aspects, advantages, and modifications are within the scope of the invention. The contents of all references, issued patents and published patent applications cited throughout this application are hereby fully incorporated by reference. The appropriate components, processes, and methods of those patents, patent applications, and other documents may be selected for the present invention and embodiments of the present invention.

Claims (59)

A composition for treating a neurodegenerative disease in a subject comprising: at least one phosphodiesterase-5 inhibitor in combination with one or more of the following agents:
Selective serotonin reuptake inhibitors;
A serotonin-norepinephrine reuptake inhibitor;
Cholinesterase inhibitor;
Dopamine agonists; or agents suitable to increase the chemical concentration of amino acids, monoamines, neuropeptides and other neurotransmitters selected from other agents capable of primary neurotransmission in the synaptic cleft.   The composition of claim 1 comprising at least one phosphodiesterase-5 inhibitor selected from the group consisting of tadalafil, vardenafil and sildenafil.   2. The composition of claim 1, comprising at least one selective serotonin reuptake inhibitor selected from the group consisting of fluvoxamine, paroxetine, citalopram, sertraline and paroxetine.   The composition of claim 1, comprising at least one serotonin-norepinephrine reuptake inhibitor selected from the group consisting of reboxetine, venlafaxine and duloxetine.   The composition of claim 1 comprising at least one cholinesterase inhibitor selected from the group consisting of tacrine and donepezil.   The composition of claim 1 comprising at least one dopamine agonist selected from the group consisting of bromocriptine, carbidopa / levodopa and pramipexole.   Suitable agents for increasing the chemical concentration of other neurotransmitters are epinephrine, norepinephrine, dopamine, serotonin, melatonin, glutamic acid, gamma aminobutyric acid, aspartic acid, glycine, adenosine, ATP, GTP, vasopressin, somatostatin , Neurotensin, luteinizing hormone, insulin, histamine, nitric oxide, carbon monoxide, acetylcholine, octopamine, tyramine, gastrin, cholecystokinin, oxytocin, neurophysin I, neurophysin II, neuropeptide Y, pancreatic poly Peptide, peptide YY, corticotropin, dynorphin, endorphin, enkephalin, secretin, motilin, glucagon, vasoactive intestinal peptide, growth hormone releasing factor, neurokinin , Neurokinin B, substance P, bombesin, are selected from the group consisting gastrin-releasing peptide, and anandamide, composition according to claim 1.   The composition of claim 1, wherein the agents are administered individually. The composition according to claim 1, wherein the drug is in a combination form selected from the following:
Patch once a week;
Monthly patch;
Long-term injection;
Combination pills; and implants. Use of a phosphodiesterase-5 inhibitor (PI-5) in the manufacture of a composition for treating a neurodegenerative disease in a subject, wherein the composition further comprises one or more of the following agents: :
Selective serotonin reuptake inhibitors;
A serotonin-norepinephrine reuptake inhibitor;
Cholinesterase inhibitor;
A dopamine agonist; or any suitable agent that increases the chemical concentration of amino acids, monoamines, neuropeptides and other neurotransmitters selected from other agents capable of primary neurotransmission in the synaptic cleft.   11. Use according to claim 10, wherein the medicaments are formulated to be administered separately.   11. Use according to claim 10, wherein the agents are formulated to be administered in the same composition.   The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia with Parkinsonian features, progressive supranuclear palsy, essential dyskinesia, or cognition Use according to claim 10, wherein the disease is symptomatic.   14. Use according to claim 13, wherein the disease is Alzheimer's disease.   14. Use according to claim 13, wherein the disease is Parkinson's disease.   14. Use according to claim 13, wherein the disease is multiple sclerosis.   14. Use according to claim 13, wherein the disease is amyotrophic lateral sclerosis.   14. Use according to claim 13, wherein the disease is frontotemporal dementia with Parkinsonian features.   14. Use according to claim 13, wherein the disease is progressive supranuclear palsy, essential dyskinesia or dementia.   14. Use according to claim 13, wherein the disease is essential dyskinesia or dementia.   14. Use according to claim 13, wherein the disease is dementia. Phosphodiesterase-5 inhibitors and the following agents:
Selective serotonin reuptake inhibitors;
A serotonin-norepinephrine reuptake inhibitor;
Cholinesterase inhibitor;
A dopamine agonist; or one or more of an agent suitable for increasing the chemical concentration of amino acids, monoamines, neuropeptides and other neurotransmitters selected from other agents capable of primary neurotransmission in the synaptic cleft A kit comprising a packaged combination, wherein each drug is formulated in a separate individual dosage form, the kit further comprising instructions for its use. Use of a phosphodiesterase-5 inhibitor in the manufacture of a formulation for treating neurodegenerative dementia in a subject, wherein the composition further comprises at least one of the following agents:
A selective serotonin reuptake inhibitor; or a cholinesterase inhibitor.   24. Use according to claim 23, wherein the phosphodiesterase-5 inhibitor is tadalafil.   24. Use according to claim 23, wherein the composition comprises fluvoxamine.   24. Use according to claim 23, wherein the composition comprises tacrine.   25. Use according to claim 24, wherein the tadalafil is at a dose ranging from 20 mg to 100 mg / day.   26. Use according to claim 25, wherein the fluvoxamine is at a dose ranging from 25 mg to 400 mg / day.   27. Use according to claim 26, wherein the tacrine is at a dose ranging from 10 mg to 160 mg / day. A composition for treating damaged skin in a subject, comprising at least one phosphodiesterase-5 inhibitor in combination with one or more of the following agents:
A selective serotonin reuptake inhibitor; or a cholinesterase inhibitor.   31. The composition of claim 30, comprising at least one phosphodiesterase-5 inhibitor selected from the group consisting of tadalafil, vardenafil and sildenafil.   32. The composition of claim 30, comprising at least one selective serotonin reuptake inhibitor selected from the group consisting of fluvoxamine, fluoxetine, citalopram, sertraline and paroxetine.   31. The composition of claim 30, comprising at least one cholinesterase inhibitor selected from the group consisting of tacrine and donepezil.   32. The composition of claim 30, wherein the agents are administered individually. 32. The composition of claim 30, wherein the drug is in a combination form selected from:
Patch once a week;
Monthly patch;
Long-term injection;
Combination pills; or implants. Use of a phosphodiesterase-5 inhibitor in the manufacture of a medicament for promoting or accelerating skin damage treatment in a subject, wherein the composition further comprises at least one or more of the following medicaments:
A selective serotonin reuptake inhibitor; or a cholinesterase inhibitor.   40. The use of claim 36, wherein the agents are formulated to be administered separately.   40. The use of claim 36, wherein the agents are formulated to be administered in the same composition.   37. Use according to claim 36, wherein the skin injury is atopy, psoriasis, contact dermatitis, acne, cancer, or vasculitis.   37. Use according to claim 36, wherein the skin damage is atopy.   37. Use according to claim 36, wherein the skin injury is psoriasis.   37. Use according to claim 36, wherein the skin injury is contact dermatitis.   37. Use according to claim 36, wherein the skin damage is acne.   37. Use according to claim 36, wherein the skin injury is cancer.   37. Use according to claim 36, wherein the skin injury is vasculitis.   37. Use according to claim 36, wherein the skin damage is the result of a traumatic process.   47. Use according to claim 46, wherein the traumatic process is selected from surgery, laceration, burns or infection.   48. Use according to claim 47, wherein the traumatic process is surgery.   48. Use according to claim 47, wherein the traumatic process is a laceration.   48. Use according to claim 47, wherein the traumatic process is a burn.   48. Use according to claim 47, wherein the traumatic process is an infection. Phosphodiesterase-5 inhibitors and the following agents:
A selective serotonin reuptake inhibitor; or a cholinesterase inhibitor;
A kit comprising a packaged combination with one or more of: wherein each agent is formulated in a separate individual dosage form, the kit further comprising instructions for its use. Use of a phosphodiesterase-5 inhibitor in the manufacture of a composition for treating skin damage in a subject, wherein the composition further comprises one or more of the following agents:
A selective serotonin reuptake inhibitor; or a cholinesterase inhibitor.   54. Use according to claim 53, wherein the phosphodiesterase-5 inhibitor is tadalafil.   54. Use according to claim 53, wherein the selective serotonin reuptake inhibitor is fluvoxamine.   54. Use according to claim 53, wherein the cholinesterase inhibitor is tacrine.   55. Use according to claim 54, wherein the tadalafil is at a dose ranging from 5 mg to 80 mg / day.   56. Use according to claim 55, wherein the fluvoxamine is at a dose ranging from 12.5 mg to 400 mg / day.   57. Use according to claim 56, wherein the tacrine is at a dose ranging from 5 mg to 60 mg / day.

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